Avian malaria,caused by parasites of the genus Plasmodium,is prevalent among wild bird populations worldwide and can have significant impact on avian health and populations.With the rise in global temperatures due to ...Avian malaria,caused by parasites of the genus Plasmodium,is prevalent among wild bird populations worldwide and can have significant impact on avian health and populations.With the rise in global temperatures due to climate change,concerns have arisen about the spread of southern malaria species,that potentially can affect previously unexposed bird populations.We studied juvenile siskins infected with two distinct malaria parasites:Plasmodium relictum(SGS1 lineage)and P.ashfordi(GRW2 lineage).While the former is common in the Northern Palearctic,the latter is primarily found in Central and Southern Africa.We assessed the impact of these infections on siskins'physiological well-being using resting metabolic rate(RMR)and interleukin-6(IL-6)levels.Changes in RMR reflect the energetic cost of disease,while IL-6 serves as a one of the inflammatory cytokines in the innate immune system's response to infection.Our experimental findings reveal distinct outcomes during the acute phase of SGS1 and GRW2 infections.Infection with SGS1 was marked by reduced RMR and IL-6 levels in siskins.A similar IL-6 pattern was observed in the GRW2 group initially,though it was not sustained.Additionally,GRW2-infected siskins showed distinct RMR dynamics compared to SGS1-infected birds.Our study did not conclusively demonstrate that tropical malaria has more severe effects on siskins.However,similarities with previous studies with SGS1 infected birds and variations in disease progression between the two experimental groups underscore the complexity of host-parasite interactions in avian malaria infections.展开更多
In this editorial,we comment on the article by Sá-Oliveira et al.We focus specifi-cally on the role of platelet-rich fibrin(PRF)in modulating innate immunity to enhance wound repair.The process of wound healing i...In this editorial,we comment on the article by Sá-Oliveira et al.We focus specifi-cally on the role of platelet-rich fibrin(PRF)in modulating innate immunity to enhance wound repair.The process of wound healing is complex and involves a coordinated series of biological events,including inflammation,cell proliferation,and tissue remodeling.The innate immune system is important in the early stages of wound repair,with inflammation being a crucial initial phase in tissue rege-neration.However,the inflammatory response should be regulated,as excessive or dysregulated inflammation can impair healing.Platelet concentrates,specifi-cally PRF,have originated as promising tools to optimize the tissue repair process.PRF is a second-generation platelet concentrate,and the release of growth factors(GFs)plays a determining role in several aspects of wound healing,including promoting cell proliferation,stimulating angiogenesis,and modulating inflam-mation.PRF forms a fibrin matrix that entraps platelets and GFs.This structure allows for their sustained release over time,which is believed to provide a more favorable microenvironment for tissue repair.Recent research by Sá-Oliveira et al has provided valuable evidence supporting the efficacy of PRF in promoting wound healing.Their study,conducted on an animal model,demonstrated that PRF-based dressings were more effective in accelerating wound closure in the early stages of the healing process,enhancing tissue repair,and modulating the inflammatory response.We explore how PRF's unique properties contribute to a more controlled and effective healing process.By examining these findings,we aim to highlight PRF's potential as a promising therapeutic strategy for improved wound management.展开更多
To the Editor:Hepatocellular carcinoma(HCC)represents the fifth most com-mon malignancy and the third cancer-related cause of death worldwide[1].Among several treatment modalities for HCC,liver transplantation(LT)is a...To the Editor:Hepatocellular carcinoma(HCC)represents the fifth most com-mon malignancy and the third cancer-related cause of death worldwide[1].Among several treatment modalities for HCC,liver transplantation(LT)is a preferred option for selected patients[2,3],which removes the tumor and targets the underlying liver disease simultaneously.To minimize the incidence of tumor recurrence,the Milan criteria and subsequently a series of expanded criteria such as UCSF and Hangzhou criteria were introduced[4-6].How-ever,tumor recurrence,which was partially ascribed to the im-paired function of antitumor immune responses following LT,still remains a pivotal obscure that hinders long-term survival[7,8].The human liver is characterized by a dual blood supply,with 80%of blood from the portal vein carrying bacterial endotoxin from the gastrointestinal tract.Liver is thus constantly exposed to a large load of intestinal antigens.展开更多
Background:Macrophages are the primary innate immune cells encountered by the invading coronaviruses,and their abilities to initiate inflammatory reactions,to main-tain the immunity homeostasis by differential polariz...Background:Macrophages are the primary innate immune cells encountered by the invading coronaviruses,and their abilities to initiate inflammatory reactions,to main-tain the immunity homeostasis by differential polarization,to train the innate immune system by epigenic modification have been reported in laboratory animal research.Methods:In the current in vitro research,murine macrophage RAW 264.7 cell were infected by mouse hepatitis virus,a coronavirus existed in mouse.At 3-,6-,12-,24-,and 48-h post infection(hpi.),the attached cells were washed with PBS and harvested in Trizol reagent.Then The harvest is subjected to transcriptome sequencing.Results:The transcriptome analysis showed the immediate(3 hpi.)up regulation of DEGs related to inflammation,like Il1b and Il6.DEGs related to M2 differential po-larization,like Irf4 showed up regulation at 24 hpi.,the late term after viral infection.In addition,DEGs related to metabolism and histone modification,like Ezh2 were de-tected,which might correlate with the trained immunity of macrophages.Conclusions:The current in vitro viral infection study showed the key innated im-munity character of macrophages,which suggested the replacement value of viral infection cells model,to reduce the animal usage in preclinical research.展开更多
RNA offers distinct advantages for molecular self-assembly as a unique and programmable biomaterial.Recently,single-stranded RNA(ssRNA)origamis,capable of self-folding into defined nanostructures within a single-stran...RNA offers distinct advantages for molecular self-assembly as a unique and programmable biomaterial.Recently,single-stranded RNA(ssRNA)origamis,capable of self-folding into defined nanostructures within a single-stranded RNA molecule,are considered a promising platform for immune recognition and therapy.Here,we utilize single-stranded rod RNA origami(Rod RNA-OG)as functional nucleic acid to synthesize valence-programmed RNA structures in a one-pot manner.We discover that the polyvalent RNA origamis are resistant to RNase degradation and can be efficiently internalized by macrophages for subsequent innate immune activation,even in the absence of any external protective agents such as lipids or polymers.The valence-programmed RNA origamis thus hold great promise as novel agonists for immunotherapy.展开更多
Chronic hepatitis B virus(HBV)infection remains a major health burden worldwide.To establish a persistence infection,HBV needs to evade both adaptive and innate immune surveillance.Multiple mechanisms for adaptive imm...Chronic hepatitis B virus(HBV)infection remains a major health burden worldwide.To establish a persistence infection,HBV needs to evade both adaptive and innate immune surveillance.Multiple mechanisms for adaptive immunity evasion have been established,but how HBV evades the innate surveillance is less clear.There are three types of host cells involving in the innate immune responses against HBV infection:Hepatocytes,hepatic nonparenchymal cells and conventional innate immune cells.Among these,hepatocytes are the only target cells that are susceptible to HBV infection and the only confirmed site where HBV replication takes place.This review focuses on the hepatocyte-intrinsic innate immunity;one of the earliest host defense responses.After entering hepatocytes,the viral components can be sensed by the cellular pattern recognition receptors.This triggers downstream antiviral responses capable of inhibiting viral replication and even degrading the viral DNA genome directly or indirectly.However,HBV has evolved a variety of sophisticated strategies to evade intracellular immune defense,resulting in the establishment of infection.Here,we provide insights into the mechanisms of the intrinsic innate immune response of hepatocytes and how HBV escapes these defense mechanisms.Hopefully,this will lay the foundation for the development of novel anti-HBV therapies.展开更多
The transcription factor Sex-determining region Y-box protein 3(SOX3)is well known for its critical roles in sex determination and cell differentiation;however,its function in antiviral innate immunity remains unexplo...The transcription factor Sex-determining region Y-box protein 3(SOX3)is well known for its critical roles in sex determination and cell differentiation;however,its function in antiviral innate immunity remains unexplored.This study uncovered how SOX3,induced by viral infections,modulates type Ⅰ interferon(IFN-Ⅰ)responses.RNA sequencing,quantitative PCR,and immunoblot analysis collectively revealed that SOX3 overexpression suppresses virus-induced interferon beta 1(IFN-β)promoter activation and significantly inhibits the expression of key antiviral interferon-stimulated genes(ISGs),including ISG15 and interferon induced protein with tetratricopeptide repeats 1(IFIT1).Conversely,the knockdown of SOX3 enhanced IFN-β production and ISGs expression,confirming its role as a negative regulator of antiviral immunity.Mechanistically,chromatin immunoprecipitation sequencing(ChIP-seq)identified SOX3 binding specifically at the AKT serine/threonine kinase 1(AKT1)locus.Further analysis demonstrated that SOX3 directly upregulates AKT1 expression,subsequently increasing phosphorylation and inactivation of the tumor suppressor phosphatase and tensin homolog(PTEN).Inactivation of PTEN inhibited interferon regulatory factor 3(IRF3)nuclear translocation,leading to reduced IFN-β expression.Thus,our findings uncover a previously uncharacterized SOX3-AKT1-PTEN signaling axis in the regulation of antiviral innate immunity,providing new insights into immune evasion strategies and highlighting potential therapeutic targets to enhance antiviral responses.展开更多
Innate lymphoid cells(ILCs),a newly identified member of the lymphoid population,play a critical role in the transition from innate to adaptive immunity in host defense.ILCs are important in mucosal barrier immunity,t...Innate lymphoid cells(ILCs),a newly identified member of the lymphoid population,play a critical role in the transition from innate to adaptive immunity in host defense.ILCs are important in mucosal barrier immunity,tissue homeostasis,and immune regulation throughout the body.Significant alterations in ILC responses in lung diseases have been observed and reported.Emerging evidence has shown that ILCs are importantly involved in the pathogenesis and development of a variety of lung diseases,i.e.,helminth infections,allergic airway inflammation,and airway hyper-responsiveness.However,as a tissue-resident cell population,the role of ILCs in the lung remains poorly characterized.In this review,we discuss the role of ILCs in lung diseases,the mechanisms underlying the ILCmediated regulation of immunity,and the therapeutic potential of modulating ILC responses.展开更多
The complement system plays a crucial role in the innate defense against common pathogens. Activation of complement leads to robust and efficient proteolytic cascades, which terminate in opsonization and lysis of the ...The complement system plays a crucial role in the innate defense against common pathogens. Activation of complement leads to robust and efficient proteolytic cascades, which terminate in opsonization and lysis of the pathogen as well as in the generation of the classical inflammatory response through the production of potent proinflammatory molecules. More recently, however, the role of complement in the immune response has been expanded due to observations that link complement activation to adaptive immune responses. It is now appreciated that complement is a functional bridge between innate and adaptive immune responses that allows an integrated host defense to pathogenic challenges. As such, a study of its functions allows insight into the molecular underpinnings of host-pathogen interactions as well as the organization and orchestration of the host immune response. This review attempts to summarize the roles that complement plays in both innate and adaptive immune responses and the consequences of these interactions on host defense.展开更多
Mitogen-activated protein kinase （MAPK） cascades play important roles in regulating plant innate immune responses. In a genetic screen to search for mutants with constitutive defense responses, we identified multipl...Mitogen-activated protein kinase （MAPK） cascades play important roles in regulating plant innate immune responses. In a genetic screen to search for mutants with constitutive defense responses, we identified multiple alleles of mpk4 and mekkl that exhibit cell death and constitutive defense responses. Bimolecular fluorescence complemen- tation （BiFC） analysis showed that both MPK4 and MEKK1 interact with MKK1 and MKK2, two closely related MAPK kinases, mkkl and mkk2 single mutant plants do not have obvious mutant phenotypes. To test whether MKK1 and MKK2 function redundantly, mkkl mkk2 double mutants were generated. The mkkl mkk2 double mutant plants die at seedling stage and the seedling-lethality phenotype is temperature-dependent. Similar to the mpk4 and mekkl mutants, the mkkl mkk2 double mutant seedlings accumulate high levels of H202, display spontaneous cell death, constitutively express Pathogenesis Related （PR） genes and exhibit pathogen resistance. In addition, activation of MPK4 by fig22 is impaired in the mkkl mkk2 double mutants, suggesting that MKK1 and MKK2 function together with MPK4 and MEKK1 in a MAP kinase cascade to negatively regulate innate immune responses in plants.展开更多
Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease in the United States and other developed countries and is expected to increase in the next few years. Emerging data suggest that some p...Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease in the United States and other developed countries and is expected to increase in the next few years. Emerging data suggest that some patients with NAFLD may progress to nonalcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma. NAFLD can also promote the development and progression of disease in other organ systems, such as the cardiovascular and endocrine (i.e. diabetes) systems. Thus, understanding the pathogenesis of NAFLD is of great clinical importance and is critical for the prevention and treatment of the disease. Although the "two-hit hypothesis" is generally accepted, the exact pathogenesis of NAFLD has not been clearly established. The liver is an important innate immune organ with large numbers of innate immune cells, including Kupffer cells (KCs), natural killer T (NKT) cells and natural killer (NK) cells. Recent data show that an imbalance in liver cytokines may be implicated in the development of fatty liver disease. For example, Th1 cytokine excess may be a common pathogenic mechanism for hepatic insulin resistance and NASH. Innate immune cells in the liver play important roles in the excessive production of hepatic Th1 cytokines in NAFLD. In addition, liver innate immune cells participate in the pathogenesis of NAFLD in other ways. For example, activated KCs can generate reactive oxygen species, which induce liver injury. This review will focus primarily on the possible effect and mechanism of KCs, NKT cells and NK cells in the development of NAFLD.展开更多
Hepatocellular carcinoma(HCC)is the most common form of liver cancer worldwide.It is caused by a variety of risk factors,most common ones being infection with hepatitis viruses,alcohol,and obesity.HCC often develops i...Hepatocellular carcinoma(HCC)is the most common form of liver cancer worldwide.It is caused by a variety of risk factors,most common ones being infection with hepatitis viruses,alcohol,and obesity.HCC often develops in the background of underlying cirrhosis,and even though a number of interventional treatment methods are currently in use,recurrence is fairly common among patients who have had a resection.Therefore,whole liver transplantation remains the most practical treatment option for HCC.Due to the growing incidence of HCC,intense research efforts are being made to understand cellular and molecular mechanisms of the disease so that novel therapeutic strategies can be developed to combat liver cancer.In recent years,it has become clear that innate immunity plays a critical role in the development of a number of liver diseases,including HCC.In particular,the activation of Toll-like receptor signaling results in the generation of immune responses that often results in the production of proinflammatory cytokines and chemokines,and could cause acute inflammation in the liver.In this review,the current knowledge on the role of innate immune responses in the development and progression of HCC is examined,and emerging therapeutic strategies based on molecular mechanisms of HCC are discussed.展开更多
Hepatitis B virus(HBV) infection is a major public healthproblem worldwide. HBV is not directly cytotoxic to infected hepatocytes; the clinical outcome of infection results from complicated interactions between the vi...Hepatitis B virus(HBV) infection is a major public healthproblem worldwide. HBV is not directly cytotoxic to infected hepatocytes; the clinical outcome of infection results from complicated interactions between the virus and the host immune system. In acute HBV infection, initiation of a broad, vigorous immune response is res-ponsible for viral clearance and self-limited inflammatory liver disease. Effective and coordinated innate and adaptive immune responses are critical for viral clearance and the development of long-lasting immunity. Chronic hepatitis B patients fail to mount efficient innate and adaptive immune responses to the virus. In particular, HBV-specific cytotoxic T cells, which are crucial for HBV clearance, are hyporesponsiveness to HBV infection. Accumulating experimental evidence obtained from the development of animal and cell line models has highlighted the importance of innate immunity in the early control of HBV spread. The virus has evolved immune escape strategies, with higher HBV loads and HBV protein concentrations associated with increasing impairment of immune function. Therefore, treatment of HBV infection requires inhibition of HBV replication and protein expression to restore the suppressed host immunity. Complicated interactions exist not only between innate and adaptive responses, but also among innate immune cells and different components of adaptive responses. Improved insight into these complex interactions are important in designing new therapeutic strategies for the treatment HBV infection. In this review, we summarize the current knowledge regarding the cross-talk between the innate and adaptive immune responses and among different immunocytes in HBV infection.展开更多
Approximately 400 million people are chronically infected with hepatitis B virus(HBV) globally despitethe widespread immunization of HBV vaccine and the development of antiviral therapies. The immunopathogenesis of HB...Approximately 400 million people are chronically infected with hepatitis B virus(HBV) globally despitethe widespread immunization of HBV vaccine and the development of antiviral therapies. The immunopathogenesis of HBV infection is initiated and driven by complexed interactions between the host immune system and the virus. Host immune responses to viral particles and proteins are regarded as the main determinants of viral clearance or persistent infection and hepatocyte injury. Innate immune system is the first defending line of host preventing from virus invasion. It is acknowledged that HBV has developed active tactics to escape innate immune recognition or actively interfere with innate immune signaling pathways and induce immunosuppression, which favor their replication. HBV reduces the expression of pattern-recognition receptors in the innate immune cells in humans. Also, HBV may interrupt different parts of antiviral signaling pathways, leading to the reduced production of antiviral cytokines such as interferons that contribute to HBV immunopathogenesis. A full comprehension of the mechanisms as to how HBV inactivates various elements of the innate immune response to initiate and maintain a persistent infection can be helpful in designing new immunotherapeutic methods for preventing and eradicating the virus. In this review, we aimed to summarize different branches the innate immune targeted by HBV infection. The review paper provides evidence that multiple components of immune responses should be activated in combination with antiviral therapy to disrupt the tolerance to HBV for eliminating HBV infection.展开更多
Inflammatory bowl disease （IBD） is a type 1 T helper cell （Th1）-mediated autoimmune disease. Various studies have revealed that environmental pathogens also play a significant role in the initiation and progressio...Inflammatory bowl disease （IBD） is a type 1 T helper cell （Th1）-mediated autoimmune disease. Various studies have revealed that environmental pathogens also play a significant role in the initiation and progression of this disease. Interestingly, the pathogenesis of IBD has been shown to be related to nitric oxide （NO） released from innate immune cells. Although NO is known to be highly toxic to the gut epithelia, there is very little information about the regulation of NO production, One major question in the etiology of IBD is how Thl cells and pathogens interact in the induction of IBD. In present study, we focused on the regulation of NO. We show that macrophages require both interferon-γ, （IFN-γ）-mediated and TLR4-mediated signals for the production of NO, which causes inflammation in the intestine and subsequently IBD. Thus, IBD is the result of concerted actions of innate immune signals, such as the binding of LPS to TLR-4, and adaptive immune signals, such as IFN-γ produced by Thl cells.展开更多
The human intestinal tract is home to an enormous bacterial flora. The host defense against microorganisms can be divided into innate and adaptive immunity. The former is the most immediate line of response to immunol...The human intestinal tract is home to an enormous bacterial flora. The host defense against microorganisms can be divided into innate and adaptive immunity. The former is the most immediate line of response to immunologic challenges presented by bacteria, viruses, and fungi. The mucosal immune system has evolved to balance the need to respond to pathogens while co-existing with commensal bacteria and food antigens. In inflammatory bowel disease （IBD）, this hyporesponsiveness or tolerance breaks down and inflammation supervenes driven by the intestinal microbial flora. Bacteria contain compounds and are recognized by a variety of receptors, including Toll-like receptors （TLRs） and NODs （a family of intracellular bacterial sensors） and are potent stimuli of innate immune responses. Several mutations in these receptors have been associated with development of IBD.展开更多
The central nervous system is recognized as an immunoprivileged site because peripheral immune cells do not typically enter it. Microglial cells are thought to be the main immune cells in brain. However, recent report...The central nervous system is recognized as an immunoprivileged site because peripheral immune cells do not typically enter it. Microglial cells are thought to be the main immune cells in brain. However, recent reports have indicated that neurons express the key players of innate immunity, including Toll-like receptors （TLRs） and their adaptor proteins （Sarml, Myd88, and Trif）, and may produce cytokines in response to pathogen infection. In the absence of an immune challenge, neuronal TLRs can detect intrinsic danger signals and modulate neuronal morphology and function. In this article, we review the recent findings on the involvement of TLRs and Sarml in controlling neuronal morphogenesis and neurodegeneration. Abnormal behaviors in TLR- and Sarml-deficient mice are also discussed.展开更多
Hepatocarcinoma(HCC) is a highly prevalent cancer worldwide and its inflammatory background was established long ago.Recent studies have shown that innate immunity is closely related to the HCC carcinogenesis.An effec...Hepatocarcinoma(HCC) is a highly prevalent cancer worldwide and its inflammatory background was established long ago.Recent studies have shown that innate immunity is closely related to the HCC carcinogenesis.An effective innate immunity response relies on the tolllike receptors(TLR) found in several different liver cells which,through different ligands and many signaling pathways can elicit,not only a pro-inflammatory but also an oncogenic or anti-oncogenic response.Our aim was to study the role of TLRs in the liver oncogenesis and as a consequence their value as potential therapeutic targets.We performed a systematic review of PubMed searching for original articles studying the relationship between HCC and TLRs until March 2015.TLR2 appears to be a fundamental stress-sensor as its absence reveals an augmented tendency to accumulate DNAdamages and to cell survival.However,pathways are still not fully understood as TLR2 up-regulation was also associated to enhanced tumorigenesis.TLR3 has a wellknown protective role influencing crucial processes like angiogenesis,cell growth or proliferation.TLR4 works as an interesting epithelial-mesenchymal transition's inducer and a promoter of cell survival probably inducing HCC carcinogenesis even though an anti-cancer role has already been observed.TLR9's influence on carcinogenesis is also controversial and despite a potential anticancer capacity,a pro-tumorigenic role is more likely.Genetic polymorphisms in some TLRs have been found and its influence on the risk of HCC has been reported.As therapeutic targets,TLRs are already in use and have a great potential.In conclusion,TLRs have been shown to be an interesting influence on the HCCs microenvironment,with TLR3 clearly determining an antitumour influence.TLR4 and TLR9 are considered to have a positive relationship with tumour development even though,in each of them anti-tumorigenic signals have been described.TLR2 presents a more ambiguous role,possibly depending on the stage of the inflammationHCC axis.展开更多
Many complex behaviors that do not require learning are displayed and are termed innate. Although traditionally the subject matter of ethology, innate behaviors offer a unique entry point for neuroscientists to dissec...Many complex behaviors that do not require learning are displayed and are termed innate. Although traditionally the subject matter of ethology, innate behaviors offer a unique entry point for neuroscientists to dissect the physiological mechanisms governing complex behaviors. Since the last century, converging evidence has implicated the hypothalamus as the central brain area that controls innate behaviors. Recent studies using cutting-edge tools have revealed that genetically-defined populations of neurons residing in distinct hypothalamic nuclei and their associated neural pathways regulate the initiation and maintenance of diverse behaviors including feeding, sleep, aggression, and parental care. Here, we review the newly-defined hypothalamic pathways that regulate each innate behavior. In addition, emerging general principles of the neural control of complex behaviors are discussed.展开更多
Even in cases where viral replication has been controlled by antiretroviral therapy for long periods of time, human immunodeficiency virus(HIV)-infected patients have several non-acquired immunodeficiency syndrome(AID...Even in cases where viral replication has been controlled by antiretroviral therapy for long periods of time, human immunodeficiency virus(HIV)-infected patients have several non-acquired immunodeficiency syndrome(AIDS) related co-morbidities, including liver disease, cardiovascular disease and neurocognitive decline, which have a clear impact on survival. It has been considered that persistent innate and acquired immune activation contributes to the pathogenesis of these non-AIDS related diseases. Immune activation has been related with several conditions, remarkably with the bacterial translocation related with the intestinal barrier damage by the HIV or by hepatitis C virus(HCV)-related liver cirrhosis. Consequently, increased morbidity and mortality must be expected in HIV-HCV coinfected patients. Disrupted gut barrier lead to an increased passage of microbial products and to an activation of the mucosal immune system and secretion of inflammatory mediators, which in turn might increase barrier dysfunction. In the present review, the intestinal barrier structure, measures of intestinal barrier dysfunction and the modifications of them in HIV monoinfection and in HIV-HCV coinfection will be considered. Both pathogenesis and the consequences for the progression of liver disease secondary to gut microbial fragment leakage and immune activation will be assessed.展开更多
基金supported by the Russian Science Foundation grant(grant Ng 20-14-00049).
文摘Avian malaria,caused by parasites of the genus Plasmodium,is prevalent among wild bird populations worldwide and can have significant impact on avian health and populations.With the rise in global temperatures due to climate change,concerns have arisen about the spread of southern malaria species,that potentially can affect previously unexposed bird populations.We studied juvenile siskins infected with two distinct malaria parasites:Plasmodium relictum(SGS1 lineage)and P.ashfordi(GRW2 lineage).While the former is common in the Northern Palearctic,the latter is primarily found in Central and Southern Africa.We assessed the impact of these infections on siskins'physiological well-being using resting metabolic rate(RMR)and interleukin-6(IL-6)levels.Changes in RMR reflect the energetic cost of disease,while IL-6 serves as a one of the inflammatory cytokines in the innate immune system's response to infection.Our experimental findings reveal distinct outcomes during the acute phase of SGS1 and GRW2 infections.Infection with SGS1 was marked by reduced RMR and IL-6 levels in siskins.A similar IL-6 pattern was observed in the GRW2 group initially,though it was not sustained.Additionally,GRW2-infected siskins showed distinct RMR dynamics compared to SGS1-infected birds.Our study did not conclusively demonstrate that tropical malaria has more severe effects on siskins.However,similarities with previous studies with SGS1 infected birds and variations in disease progression between the two experimental groups underscore the complexity of host-parasite interactions in avian malaria infections.
基金Supported by The Oman Ministry of Higher Education,Research,and Innovation,No.BFP/RGP/HSS/24/015.
文摘In this editorial,we comment on the article by Sá-Oliveira et al.We focus specifi-cally on the role of platelet-rich fibrin(PRF)in modulating innate immunity to enhance wound repair.The process of wound healing is complex and involves a coordinated series of biological events,including inflammation,cell proliferation,and tissue remodeling.The innate immune system is important in the early stages of wound repair,with inflammation being a crucial initial phase in tissue rege-neration.However,the inflammatory response should be regulated,as excessive or dysregulated inflammation can impair healing.Platelet concentrates,specifi-cally PRF,have originated as promising tools to optimize the tissue repair process.PRF is a second-generation platelet concentrate,and the release of growth factors(GFs)plays a determining role in several aspects of wound healing,including promoting cell proliferation,stimulating angiogenesis,and modulating inflam-mation.PRF forms a fibrin matrix that entraps platelets and GFs.This structure allows for their sustained release over time,which is believed to provide a more favorable microenvironment for tissue repair.Recent research by Sá-Oliveira et al has provided valuable evidence supporting the efficacy of PRF in promoting wound healing.Their study,conducted on an animal model,demonstrated that PRF-based dressings were more effective in accelerating wound closure in the early stages of the healing process,enhancing tissue repair,and modulating the inflammatory response.We explore how PRF's unique properties contribute to a more controlled and effective healing process.By examining these findings,we aim to highlight PRF's potential as a promising therapeutic strategy for improved wound management.
基金supported by grants from the National Natural Science Foundation of China(82300742)Zhejiang Provincial Natural Science Foundation of China(LQ22H160052).
文摘To the Editor:Hepatocellular carcinoma(HCC)represents the fifth most com-mon malignancy and the third cancer-related cause of death worldwide[1].Among several treatment modalities for HCC,liver transplantation(LT)is a preferred option for selected patients[2,3],which removes the tumor and targets the underlying liver disease simultaneously.To minimize the incidence of tumor recurrence,the Milan criteria and subsequently a series of expanded criteria such as UCSF and Hangzhou criteria were introduced[4-6].How-ever,tumor recurrence,which was partially ascribed to the im-paired function of antitumor immune responses following LT,still remains a pivotal obscure that hinders long-term survival[7,8].The human liver is characterized by a dual blood supply,with 80%of blood from the portal vein carrying bacterial endotoxin from the gastrointestinal tract.Liver is thus constantly exposed to a large load of intestinal antigens.
基金CAMs innovation Fund for Medical Sciences,Grant/Award Number:2022-12M-CoV19-005National Key Projects,Grant/Award Number:2023YFF0724900 and 2021YFF0702802。
文摘Background:Macrophages are the primary innate immune cells encountered by the invading coronaviruses,and their abilities to initiate inflammatory reactions,to main-tain the immunity homeostasis by differential polarization,to train the innate immune system by epigenic modification have been reported in laboratory animal research.Methods:In the current in vitro research,murine macrophage RAW 264.7 cell were infected by mouse hepatitis virus,a coronavirus existed in mouse.At 3-,6-,12-,24-,and 48-h post infection(hpi.),the attached cells were washed with PBS and harvested in Trizol reagent.Then The harvest is subjected to transcriptome sequencing.Results:The transcriptome analysis showed the immediate(3 hpi.)up regulation of DEGs related to inflammation,like Il1b and Il6.DEGs related to M2 differential po-larization,like Irf4 showed up regulation at 24 hpi.,the late term after viral infection.In addition,DEGs related to metabolism and histone modification,like Ezh2 were de-tected,which might correlate with the trained immunity of macrophages.Conclusions:The current in vitro viral infection study showed the key innated im-munity character of macrophages,which suggested the replacement value of viral infection cells model,to reduce the animal usage in preclinical research.
基金supported by the National Key Research and Development Program of China(Nos.2021YFF1200300,2020YFA0909000)National Natural Science Foundation of China(Nos.22025404,32471426)+3 种基金Innovative Research Group of High-Level Local Universities in Shanghai(No.SHSMU-ZLCX20212602)Natural Science Foundation of Shanghai(No.23ZR1438700)Shanghai Municipal Health Commission(No.2022JC027)Shanghai Sailing Program(No.22YF1424400)。
文摘RNA offers distinct advantages for molecular self-assembly as a unique and programmable biomaterial.Recently,single-stranded RNA(ssRNA)origamis,capable of self-folding into defined nanostructures within a single-stranded RNA molecule,are considered a promising platform for immune recognition and therapy.Here,we utilize single-stranded rod RNA origami(Rod RNA-OG)as functional nucleic acid to synthesize valence-programmed RNA structures in a one-pot manner.We discover that the polyvalent RNA origamis are resistant to RNase degradation and can be efficiently internalized by macrophages for subsequent innate immune activation,even in the absence of any external protective agents such as lipids or polymers.The valence-programmed RNA origamis thus hold great promise as novel agonists for immunotherapy.
基金Supported by Shenzhen Medical Research Fund,No.D2301010Shenzhen Science and Technology Program,No.RCYX20231211090346060。
文摘Chronic hepatitis B virus(HBV)infection remains a major health burden worldwide.To establish a persistence infection,HBV needs to evade both adaptive and innate immune surveillance.Multiple mechanisms for adaptive immunity evasion have been established,but how HBV evades the innate surveillance is less clear.There are three types of host cells involving in the innate immune responses against HBV infection:Hepatocytes,hepatic nonparenchymal cells and conventional innate immune cells.Among these,hepatocytes are the only target cells that are susceptible to HBV infection and the only confirmed site where HBV replication takes place.This review focuses on the hepatocyte-intrinsic innate immunity;one of the earliest host defense responses.After entering hepatocytes,the viral components can be sensed by the cellular pattern recognition receptors.This triggers downstream antiviral responses capable of inhibiting viral replication and even degrading the viral DNA genome directly or indirectly.However,HBV has evolved a variety of sophisticated strategies to evade intracellular immune defense,resulting in the establishment of infection.Here,we provide insights into the mechanisms of the intrinsic innate immune response of hepatocytes and how HBV escapes these defense mechanisms.Hopefully,this will lay the foundation for the development of novel anti-HBV therapies.
基金supported by the Central Guidance on Local Science and Technology Development Fund of Tibet(Grant No.XZ202301YD0040C)the National Natural Science Foundation of China(Grant No.32260173)the Youth Program of Natural Science Foundation of Henan Province(Grant No.252300420594).
文摘The transcription factor Sex-determining region Y-box protein 3(SOX3)is well known for its critical roles in sex determination and cell differentiation;however,its function in antiviral innate immunity remains unexplored.This study uncovered how SOX3,induced by viral infections,modulates type Ⅰ interferon(IFN-Ⅰ)responses.RNA sequencing,quantitative PCR,and immunoblot analysis collectively revealed that SOX3 overexpression suppresses virus-induced interferon beta 1(IFN-β)promoter activation and significantly inhibits the expression of key antiviral interferon-stimulated genes(ISGs),including ISG15 and interferon induced protein with tetratricopeptide repeats 1(IFIT1).Conversely,the knockdown of SOX3 enhanced IFN-β production and ISGs expression,confirming its role as a negative regulator of antiviral immunity.Mechanistically,chromatin immunoprecipitation sequencing(ChIP-seq)identified SOX3 binding specifically at the AKT serine/threonine kinase 1(AKT1)locus.Further analysis demonstrated that SOX3 directly upregulates AKT1 expression,subsequently increasing phosphorylation and inactivation of the tumor suppressor phosphatase and tensin homolog(PTEN).Inactivation of PTEN inhibited interferon regulatory factor 3(IRF3)nuclear translocation,leading to reduced IFN-β expression.Thus,our findings uncover a previously uncharacterized SOX3-AKT1-PTEN signaling axis in the regulation of antiviral innate immunity,providing new insights into immune evasion strategies and highlighting potential therapeutic targets to enhance antiviral responses.
基金supported by the USA National Institutes of Health Grant R01-HL-079669(J.F.)USA National Institutes of Health Grant R01-HL076179(J.F.)+2 种基金USA National Institutes of Health Grant R56-HL-123882(J.F.)USA VA Merit Award 1I01BX002729(J.F.)the Zhejiang Provincial Program for the Cultivation of High-level Innovative Health Talents(Q.S.)
文摘Innate lymphoid cells(ILCs),a newly identified member of the lymphoid population,play a critical role in the transition from innate to adaptive immunity in host defense.ILCs are important in mucosal barrier immunity,tissue homeostasis,and immune regulation throughout the body.Significant alterations in ILC responses in lung diseases have been observed and reported.Emerging evidence has shown that ILCs are importantly involved in the pathogenesis and development of a variety of lung diseases,i.e.,helminth infections,allergic airway inflammation,and airway hyper-responsiveness.However,as a tissue-resident cell population,the role of ILCs in the lung remains poorly characterized.In this review,we discuss the role of ILCs in lung diseases,the mechanisms underlying the ILCmediated regulation of immunity,and the therapeutic potential of modulating ILC responses.
文摘The complement system plays a crucial role in the innate defense against common pathogens. Activation of complement leads to robust and efficient proteolytic cascades, which terminate in opsonization and lysis of the pathogen as well as in the generation of the classical inflammatory response through the production of potent proinflammatory molecules. More recently, however, the role of complement in the immune response has been expanded due to observations that link complement activation to adaptive immune responses. It is now appreciated that complement is a functional bridge between innate and adaptive immune responses that allows an integrated host defense to pathogenic challenges. As such, a study of its functions allows insight into the molecular underpinnings of host-pathogen interactions as well as the organization and orchestration of the host immune response. This review attempts to summarize the roles that complement plays in both innate and adaptive immune responses and the consequences of these interactions on host defense.
文摘Mitogen-activated protein kinase （MAPK） cascades play important roles in regulating plant innate immune responses. In a genetic screen to search for mutants with constitutive defense responses, we identified multiple alleles of mpk4 and mekkl that exhibit cell death and constitutive defense responses. Bimolecular fluorescence complemen- tation （BiFC） analysis showed that both MPK4 and MEKK1 interact with MKK1 and MKK2, two closely related MAPK kinases, mkkl and mkk2 single mutant plants do not have obvious mutant phenotypes. To test whether MKK1 and MKK2 function redundantly, mkkl mkk2 double mutants were generated. The mkkl mkk2 double mutant plants die at seedling stage and the seedling-lethality phenotype is temperature-dependent. Similar to the mpk4 and mekkl mutants, the mkkl mkk2 double mutant seedlings accumulate high levels of H202, display spontaneous cell death, constitutively express Pathogenesis Related （PR） genes and exhibit pathogen resistance. In addition, activation of MPK4 by fig22 is impaired in the mkkl mkk2 double mutants, suggesting that MKK1 and MKK2 function together with MPK4 and MEKK1 in a MAP kinase cascade to negatively regulate innate immune responses in plants.
基金Supported by Beijing Municipal Laboratory for Liver Protection and Regulation of Regeneration, Beijing, China
文摘Nonalcoholic fatty liver disease (NAFLD) has become the most common liver disease in the United States and other developed countries and is expected to increase in the next few years. Emerging data suggest that some patients with NAFLD may progress to nonalcoholic steatohepatitis (NASH), cirrhosis and even hepatocellular carcinoma. NAFLD can also promote the development and progression of disease in other organ systems, such as the cardiovascular and endocrine (i.e. diabetes) systems. Thus, understanding the pathogenesis of NAFLD is of great clinical importance and is critical for the prevention and treatment of the disease. Although the "two-hit hypothesis" is generally accepted, the exact pathogenesis of NAFLD has not been clearly established. The liver is an important innate immune organ with large numbers of innate immune cells, including Kupffer cells (KCs), natural killer T (NKT) cells and natural killer (NK) cells. Recent data show that an imbalance in liver cytokines may be implicated in the development of fatty liver disease. For example, Th1 cytokine excess may be a common pathogenic mechanism for hepatic insulin resistance and NASH. Innate immune cells in the liver play important roles in the excessive production of hepatic Th1 cytokines in NAFLD. In addition, liver innate immune cells participate in the pathogenesis of NAFLD in other ways. For example, activated KCs can generate reactive oxygen species, which induce liver injury. This review will focus primarily on the possible effect and mechanism of KCs, NKT cells and NK cells in the development of NAFLD.
文摘Hepatocellular carcinoma(HCC)is the most common form of liver cancer worldwide.It is caused by a variety of risk factors,most common ones being infection with hepatitis viruses,alcohol,and obesity.HCC often develops in the background of underlying cirrhosis,and even though a number of interventional treatment methods are currently in use,recurrence is fairly common among patients who have had a resection.Therefore,whole liver transplantation remains the most practical treatment option for HCC.Due to the growing incidence of HCC,intense research efforts are being made to understand cellular and molecular mechanisms of the disease so that novel therapeutic strategies can be developed to combat liver cancer.In recent years,it has become clear that innate immunity plays a critical role in the development of a number of liver diseases,including HCC.In particular,the activation of Toll-like receptor signaling results in the generation of immune responses that often results in the production of proinflammatory cytokines and chemokines,and could cause acute inflammation in the liver.In this review,the current knowledge on the role of innate immune responses in the development and progression of HCC is examined,and emerging therapeutic strategies based on molecular mechanisms of HCC are discussed.
基金Supported by Grants of Yantai Science and Technology Plan Project,No.2012116
文摘Hepatitis B virus(HBV) infection is a major public healthproblem worldwide. HBV is not directly cytotoxic to infected hepatocytes; the clinical outcome of infection results from complicated interactions between the virus and the host immune system. In acute HBV infection, initiation of a broad, vigorous immune response is res-ponsible for viral clearance and self-limited inflammatory liver disease. Effective and coordinated innate and adaptive immune responses are critical for viral clearance and the development of long-lasting immunity. Chronic hepatitis B patients fail to mount efficient innate and adaptive immune responses to the virus. In particular, HBV-specific cytotoxic T cells, which are crucial for HBV clearance, are hyporesponsiveness to HBV infection. Accumulating experimental evidence obtained from the development of animal and cell line models has highlighted the importance of innate immunity in the early control of HBV spread. The virus has evolved immune escape strategies, with higher HBV loads and HBV protein concentrations associated with increasing impairment of immune function. Therefore, treatment of HBV infection requires inhibition of HBV replication and protein expression to restore the suppressed host immunity. Complicated interactions exist not only between innate and adaptive responses, but also among innate immune cells and different components of adaptive responses. Improved insight into these complex interactions are important in designing new therapeutic strategies for the treatment HBV infection. In this review, we summarize the current knowledge regarding the cross-talk between the innate and adaptive immune responses and among different immunocytes in HBV infection.
文摘Approximately 400 million people are chronically infected with hepatitis B virus(HBV) globally despitethe widespread immunization of HBV vaccine and the development of antiviral therapies. The immunopathogenesis of HBV infection is initiated and driven by complexed interactions between the host immune system and the virus. Host immune responses to viral particles and proteins are regarded as the main determinants of viral clearance or persistent infection and hepatocyte injury. Innate immune system is the first defending line of host preventing from virus invasion. It is acknowledged that HBV has developed active tactics to escape innate immune recognition or actively interfere with innate immune signaling pathways and induce immunosuppression, which favor their replication. HBV reduces the expression of pattern-recognition receptors in the innate immune cells in humans. Also, HBV may interrupt different parts of antiviral signaling pathways, leading to the reduced production of antiviral cytokines such as interferons that contribute to HBV immunopathogenesis. A full comprehension of the mechanisms as to how HBV inactivates various elements of the innate immune response to initiate and maintain a persistent infection can be helpful in designing new immunotherapeutic methods for preventing and eradicating the virus. In this review, we aimed to summarize different branches the innate immune targeted by HBV infection. The review paper provides evidence that multiple components of immune responses should be activated in combination with antiviral therapy to disrupt the tolerance to HBV for eliminating HBV infection.
文摘Inflammatory bowl disease （IBD） is a type 1 T helper cell （Th1）-mediated autoimmune disease. Various studies have revealed that environmental pathogens also play a significant role in the initiation and progression of this disease. Interestingly, the pathogenesis of IBD has been shown to be related to nitric oxide （NO） released from innate immune cells. Although NO is known to be highly toxic to the gut epithelia, there is very little information about the regulation of NO production, One major question in the etiology of IBD is how Thl cells and pathogens interact in the induction of IBD. In present study, we focused on the regulation of NO. We show that macrophages require both interferon-γ, （IFN-γ）-mediated and TLR4-mediated signals for the production of NO, which causes inflammation in the intestine and subsequently IBD. Thus, IBD is the result of concerted actions of innate immune signals, such as the binding of LPS to TLR-4, and adaptive immune signals, such as IFN-γ produced by Thl cells.
文摘The human intestinal tract is home to an enormous bacterial flora. The host defense against microorganisms can be divided into innate and adaptive immunity. The former is the most immediate line of response to immunologic challenges presented by bacteria, viruses, and fungi. The mucosal immune system has evolved to balance the need to respond to pathogens while co-existing with commensal bacteria and food antigens. In inflammatory bowel disease （IBD）, this hyporesponsiveness or tolerance breaks down and inflammation supervenes driven by the intestinal microbial flora. Bacteria contain compounds and are recognized by a variety of receptors, including Toll-like receptors （TLRs） and NODs （a family of intracellular bacterial sensors） and are potent stimuli of innate immune responses. Several mutations in these receptors have been associated with development of IBD.
基金supported by grants from Academia Sinica (AS 103-TP-B05)he Ministry of Science and Technology (MOST 102-2321-B-001-054 and 102-2321-B-001-029)
文摘The central nervous system is recognized as an immunoprivileged site because peripheral immune cells do not typically enter it. Microglial cells are thought to be the main immune cells in brain. However, recent reports have indicated that neurons express the key players of innate immunity, including Toll-like receptors （TLRs） and their adaptor proteins （Sarml, Myd88, and Trif）, and may produce cytokines in response to pathogen infection. In the absence of an immune challenge, neuronal TLRs can detect intrinsic danger signals and modulate neuronal morphology and function. In this article, we review the recent findings on the involvement of TLRs and Sarml in controlling neuronal morphogenesis and neurodegeneration. Abnormal behaviors in TLR- and Sarml-deficient mice are also discussed.
文摘Hepatocarcinoma(HCC) is a highly prevalent cancer worldwide and its inflammatory background was established long ago.Recent studies have shown that innate immunity is closely related to the HCC carcinogenesis.An effective innate immunity response relies on the tolllike receptors(TLR) found in several different liver cells which,through different ligands and many signaling pathways can elicit,not only a pro-inflammatory but also an oncogenic or anti-oncogenic response.Our aim was to study the role of TLRs in the liver oncogenesis and as a consequence their value as potential therapeutic targets.We performed a systematic review of PubMed searching for original articles studying the relationship between HCC and TLRs until March 2015.TLR2 appears to be a fundamental stress-sensor as its absence reveals an augmented tendency to accumulate DNAdamages and to cell survival.However,pathways are still not fully understood as TLR2 up-regulation was also associated to enhanced tumorigenesis.TLR3 has a wellknown protective role influencing crucial processes like angiogenesis,cell growth or proliferation.TLR4 works as an interesting epithelial-mesenchymal transition's inducer and a promoter of cell survival probably inducing HCC carcinogenesis even though an anti-cancer role has already been observed.TLR9's influence on carcinogenesis is also controversial and despite a potential anticancer capacity,a pro-tumorigenic role is more likely.Genetic polymorphisms in some TLRs have been found and its influence on the risk of HCC has been reported.As therapeutic targets,TLRs are already in use and have a great potential.In conclusion,TLRs have been shown to be an interesting influence on the HCCs microenvironment,with TLR3 clearly determining an antitumour influence.TLR4 and TLR9 are considered to have a positive relationship with tumour development even though,in each of them anti-tumorigenic signals have been described.TLR2 presents a more ambiguous role,possibly depending on the stage of the inflammationHCC axis.
基金supported by the Strategic Priority Research Program of the Chinese Academy of Sciences, China (XDB02030005)
文摘Many complex behaviors that do not require learning are displayed and are termed innate. Although traditionally the subject matter of ethology, innate behaviors offer a unique entry point for neuroscientists to dissect the physiological mechanisms governing complex behaviors. Since the last century, converging evidence has implicated the hypothalamus as the central brain area that controls innate behaviors. Recent studies using cutting-edge tools have revealed that genetically-defined populations of neurons residing in distinct hypothalamic nuclei and their associated neural pathways regulate the initiation and maintenance of diverse behaviors including feeding, sleep, aggression, and parental care. Here, we review the newly-defined hypothalamic pathways that regulate each innate behavior. In addition, emerging general principles of the neural control of complex behaviors are discussed.
基金Supported by Instituto de Salud Carlos III,Plan Nacional de I+D+I 2008-2011No.PI11/00605 and Plan Estatal de I+D+I 2013-2016+1 种基金No.PI14/01779Co-financed by FEDER(Fondo Europeo de Desarrollo Regional)
文摘Even in cases where viral replication has been controlled by antiretroviral therapy for long periods of time, human immunodeficiency virus(HIV)-infected patients have several non-acquired immunodeficiency syndrome(AIDS) related co-morbidities, including liver disease, cardiovascular disease and neurocognitive decline, which have a clear impact on survival. It has been considered that persistent innate and acquired immune activation contributes to the pathogenesis of these non-AIDS related diseases. Immune activation has been related with several conditions, remarkably with the bacterial translocation related with the intestinal barrier damage by the HIV or by hepatitis C virus(HCV)-related liver cirrhosis. Consequently, increased morbidity and mortality must be expected in HIV-HCV coinfected patients. Disrupted gut barrier lead to an increased passage of microbial products and to an activation of the mucosal immune system and secretion of inflammatory mediators, which in turn might increase barrier dysfunction. In the present review, the intestinal barrier structure, measures of intestinal barrier dysfunction and the modifications of them in HIV monoinfection and in HIV-HCV coinfection will be considered. Both pathogenesis and the consequences for the progression of liver disease secondary to gut microbial fragment leakage and immune activation will be assessed.
