Increased expression of angiotensin-converting enzyme(ACE)by myeloid lineage cells strongly increases the immune activity of these cells,as observed in ACE10/10 mice,which exhibit a marked increase in antitumor and an...Increased expression of angiotensin-converting enzyme(ACE)by myeloid lineage cells strongly increases the immune activity of these cells,as observed in ACE10/10 mice,which exhibit a marked increase in antitumor and antibactericidal immunity.We report that peroxisome proliferator-activated receptor alpha(PPARα),a transcription factor that regulates genes critical for lipid metabolism,is a key molecule in the enhanced macrophage function induced by ACE.Here,we used a Cre-LoxP approach with LysM-Cre to create a modified ACE10/10 mouse line in which macrophages continue to generate abundant ACE but in which monocyte and macrophage PPARαexpression is selectively suppressed.These mice,termed A10-PPARα-Cre,have significantly increased growth of B16-F10 tumors compared with ACE10/10 mice with Cre expression.PPARαdepletion impaired cytokine production and antigen-presenting activity in ACE-expressing macrophages,resulting in reduced tumor antigen-specific CD8^(+)T-cell generation.Additionally,the elevated bactericidal resistance typical of ACE10/10 mice was significantly reduced in A10-PPARα-Cre mice,such that these mice resembled WT mice in their resistance to methicillin-resistant Staphylococcus aureus(MRSA)infection.THP-1 cells expressing increased ACE(termed THP-1-ACE)constitute a human macrophage model with increased PPARαthat shows enhanced cytotoxicity against tumor cells and better phagocytosis and killing of MRSA.RNA silencing of PPARα in THP-1-ACE cells reduced both tumor cell death and bacterial phagocytosis and clearance.In contrast,the in vivo administration of pemafibrate,a specific agonist of PPARα,to WT and A10-PPARα-Cre mice reduced B16-F10 tumor growth by 24.5% and 25.8%,respectively,but pemafibrate reduced tumors by 57.8% in ACE10/10 mice.With pemafibrate,the number of antitumor CD8^(+)T cells was significantly lower in A10-PPARα-Cre mice than in ACE10/10 mice.We conclude that PPARα is important in the immune system of myeloid cells,including wild-type cells,and that its increased expression by ACE-expressing macrophages in ACE10/10 mice is indispensable for ACE-dependent functional upregulation of macrophages in both mice and human cells.展开更多
Neutrophils are innate immune cells that function predominantly against pathogens,while recent studies have revealed additional crucial roles in various diseases,including cancers[1–3].For instance,neutrophils expres...Neutrophils are innate immune cells that function predominantly against pathogens,while recent studies have revealed additional crucial roles in various diseases,including cancers[1–3].For instance,neutrophils expressing the co-inhibitory molecule programmed death-ligand 1(PD-L1)were identified as novel immunosuppressive myeloid cells that impair cytotoxic T cell(CTL)activity via programmed cell death protein 1(PD-1)/PD-L1 interaction[4,5].Although some stimuli have been identified,it is still unclear whether the nucleic acid sensing system(NAS)participates in PD-L1 upregulation in neutrophils[6].Here,we report that increased cell-free nucleic acid(CFNA)upregulates PD-L1 expression via intracellular Toll-like receptor(TLR)activation in neutrophils following tumor expansion.展开更多
基金supported by NIH R01 AI164519-03(KEB),R01 HL155346-01A1(JVE)American Heart Association’s Career Development award 23CDA1052548(DYC)+1 种基金the Cedars-Sinai Department of Pathology and Laboratory Medicine Minigrants(KEB,ZK)the Cedars-Sinai Startup Fund 233040(ZK).
文摘Increased expression of angiotensin-converting enzyme(ACE)by myeloid lineage cells strongly increases the immune activity of these cells,as observed in ACE10/10 mice,which exhibit a marked increase in antitumor and antibactericidal immunity.We report that peroxisome proliferator-activated receptor alpha(PPARα),a transcription factor that regulates genes critical for lipid metabolism,is a key molecule in the enhanced macrophage function induced by ACE.Here,we used a Cre-LoxP approach with LysM-Cre to create a modified ACE10/10 mouse line in which macrophages continue to generate abundant ACE but in which monocyte and macrophage PPARαexpression is selectively suppressed.These mice,termed A10-PPARα-Cre,have significantly increased growth of B16-F10 tumors compared with ACE10/10 mice with Cre expression.PPARαdepletion impaired cytokine production and antigen-presenting activity in ACE-expressing macrophages,resulting in reduced tumor antigen-specific CD8^(+)T-cell generation.Additionally,the elevated bactericidal resistance typical of ACE10/10 mice was significantly reduced in A10-PPARα-Cre mice,such that these mice resembled WT mice in their resistance to methicillin-resistant Staphylococcus aureus(MRSA)infection.THP-1 cells expressing increased ACE(termed THP-1-ACE)constitute a human macrophage model with increased PPARαthat shows enhanced cytotoxicity against tumor cells and better phagocytosis and killing of MRSA.RNA silencing of PPARα in THP-1-ACE cells reduced both tumor cell death and bacterial phagocytosis and clearance.In contrast,the in vivo administration of pemafibrate,a specific agonist of PPARα,to WT and A10-PPARα-Cre mice reduced B16-F10 tumor growth by 24.5% and 25.8%,respectively,but pemafibrate reduced tumors by 57.8% in ACE10/10 mice.With pemafibrate,the number of antitumor CD8^(+)T cells was significantly lower in A10-PPARα-Cre mice than in ACE10/10 mice.We conclude that PPARα is important in the immune system of myeloid cells,including wild-type cells,and that its increased expression by ACE-expressing macrophages in ACE10/10 mice is indispensable for ACE-dependent functional upregulation of macrophages in both mice and human cells.
基金supported by the National Institutes of Health grants(R01AI164519,2R01CA151610,R21CA280458)American Heart Association’s Career Development award(23CDA1052548)U.S.Department of Defense(W81XWH-18-1-0067)and the Glazer Foundation.
文摘Neutrophils are innate immune cells that function predominantly against pathogens,while recent studies have revealed additional crucial roles in various diseases,including cancers[1–3].For instance,neutrophils expressing the co-inhibitory molecule programmed death-ligand 1(PD-L1)were identified as novel immunosuppressive myeloid cells that impair cytotoxic T cell(CTL)activity via programmed cell death protein 1(PD-1)/PD-L1 interaction[4,5].Although some stimuli have been identified,it is still unclear whether the nucleic acid sensing system(NAS)participates in PD-L1 upregulation in neutrophils[6].Here,we report that increased cell-free nucleic acid(CFNA)upregulates PD-L1 expression via intracellular Toll-like receptor(TLR)activation in neutrophils following tumor expansion.
