In a landmark study recently published in Nature,1 Wei and colleagues demonstrate that the activation of GSDMD by the cytosolic lipopolysaccharide(LPS)sensor caspase-11 triggers blood–brain barrier(BBB)breakdown upon...In a landmark study recently published in Nature,1 Wei and colleagues demonstrate that the activation of GSDMD by the cytosolic lipopolysaccharide(LPS)sensor caspase-11 triggers blood–brain barrier(BBB)breakdown upon LPS challenge independent of TLR4-induced cytokine release.Their work identifies the noncanonical inflammasome and GSDMD pore formation as a potential target for treating central nervous system(CNS)disorders associated with inflammatory BBB dysfunction.展开更多
Dear Editor,A rapid immune response to signals released from pathogens and injuries is critical for maintaining tissue integrity and restoring homeostasis.This response is largely mediated by the concerted action of p...Dear Editor,A rapid immune response to signals released from pathogens and injuries is critical for maintaining tissue integrity and restoring homeostasis.This response is largely mediated by the concerted action of pattern recognition receptors(PRRs).Such cooperativity has been described for Toll-like receptors(TLRs)and NACHT,LRR,and pyrin domain-containing protein 3(NLRP3),but the underlying molecular mechanisms remain incompletely understood.Inflammasomes are multi-protein complexes defined by a cytosolic innate immune sensor,usually a PRR,which recruits the adaptor molecule apoptosis-associated speck-like protein containing a caspase-recruitment domain(ASC)to activate the effector caspase-1 leading to the release of matured IL-1βand IL-18.Active caspase-1 further cleaves gasdermin D(GSDMD)allowing the N-terminal domain of GSDMD(GSDMD-N)to form pores in the plasma membrane,thus facilitating the release of matured IL-1βand IL-18.Pore-forming GSDMD-N further induces pyroptosis,an inflammatory form of cell death.展开更多
基金supported by grants from the Deutsche Forschungsgemeinschaft(DFG,CRC 1123[B3],DI-722/16-1[ID:428668490],DI 722/21-1Munich Cluster for Systems Neurology[SyNergy,EXC 2145])a grant from the Leducq Foundation,and the Vascular Dementia Research Foundation.Y.Asare was supported by DFG(CRC 1123[B3],AS 575/1-1).
文摘In a landmark study recently published in Nature,1 Wei and colleagues demonstrate that the activation of GSDMD by the cytosolic lipopolysaccharide(LPS)sensor caspase-11 triggers blood–brain barrier(BBB)breakdown upon LPS challenge independent of TLR4-induced cytokine release.Their work identifies the noncanonical inflammasome and GSDMD pore formation as a potential target for treating central nervous system(CNS)disorders associated with inflammatory BBB dysfunction.
基金Deutsche Forschungsgemeinschaft(DFG CRC 1123[B3],DI-722/16-1[ID:428668490]Munich Cluster for Systems Neurology[SyNergy,EXC 2145])Vascular Dementia Research Foundation to M.Dichgans.Y.Asare was supported by DFG(CRC 1123[B3])+1 种基金J.Bernhagen received funding from DFG/CRC 1123[A3],DFG INST 409/209-1 FUGG,and DFG(EXC 2145 SyNergy)C.Weber was supported by DFG(CRC 1123[A01&A10]).
文摘Dear Editor,A rapid immune response to signals released from pathogens and injuries is critical for maintaining tissue integrity and restoring homeostasis.This response is largely mediated by the concerted action of pattern recognition receptors(PRRs).Such cooperativity has been described for Toll-like receptors(TLRs)and NACHT,LRR,and pyrin domain-containing protein 3(NLRP3),but the underlying molecular mechanisms remain incompletely understood.Inflammasomes are multi-protein complexes defined by a cytosolic innate immune sensor,usually a PRR,which recruits the adaptor molecule apoptosis-associated speck-like protein containing a caspase-recruitment domain(ASC)to activate the effector caspase-1 leading to the release of matured IL-1βand IL-18.Active caspase-1 further cleaves gasdermin D(GSDMD)allowing the N-terminal domain of GSDMD(GSDMD-N)to form pores in the plasma membrane,thus facilitating the release of matured IL-1βand IL-18.Pore-forming GSDMD-N further induces pyroptosis,an inflammatory form of cell death.
