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
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.
