Peroxisome proliferator-activated receptor alpha is essential factor in enhanced macrophage immune function induced by angiotensin converting enzyme.

Autor:	Saito S; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA., Cao D; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA., Bernstein EA; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA., Jones AE; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA., Rios A; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA., Hoshi AO; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.; Graduate School of Comprehensive Human Science, University of Tsukuba, Tsukuba, Ibaraki 3058577, Japan., Stotland AB; Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA., Nishi EE; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.; Department of Physiology, São Paulo School of Medicine, Universidade Federal de São Paulo, Rua Botucatu, 862 terreo, Sao Paulo, 04023-062, Brazil., Shibata T; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA., Ahmed F; Division of Gastroenterology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA., Van Eyk JE; Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA., Divakaruni A; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA 90095, USA., Khan Z; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA., Bernstein KE; Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.; Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA.
Jazyk:	angličtina
Zdroj:	Research square [Res Sq] 2024 Apr 22. Date of Electronic Publication: 2024 Apr 22.
DOI:	10.21203/rs.3.rs-4255086/v1
Abstrakt:	An upregulation of angiotensin-converting enzyme (ACE) expression strengthens the immune activity of myeloid lineage cells as a natural functional regulation mechanism in our immunity. ACE10/10 mice, possessing increased ACE expression in macrophages, exhibit enhanced anti-tumor immunity and anti-bactericidal effects compared to those of wild type (WT) mice, while the detailed molecular mechanism has not been elucidated yet. In this report, we demonstrate that peroxisome proliferator-activated receptor alpha (PPARα) is a key molecule in the functional upregulation of macrophages induced by ACE. The expression of PPARα, a transcription factor regulating fatty acid metabolism-associated gene expressions, was upregulated in ACE-overexpressing macrophages. To pinpoint the role of PPARα in the enhanced immune function of ACE-overexpressing macrophages, we established a line with myeloid lineage-selective PPARα depletion employing the Lysozyme 2 (LysM)-Cre system based on ACE 10/10 mice (named A10-PPARα-Cre). Interestingly, A10-PPARα-Cre mice exhibited larger B16-F10-originated tumors than original ACE 10/10 mice. PPARα depletion impaired cytokine production and antigen-presenting activity in ACE-overexpressing macrophages, resulting in reduced tumor antigen-specific CD8+ T cell activity. Additionally, the anti-bactericidal effect was also impaired in A10-PPARα-Cre mice, resulting in similar bacterial colonization to WT mice in Methicillin-Resistant Staphylococcus aureus (MRSA) infection. PPARα depletion downregulated phagocytic activity and bacteria killing in ACE-overexpressing macrophages. Moreover, THP-1-ACE-derived macrophages, as a human model, expressing upregulated PPARα exhibited enhanced cytotoxicity against B16-F10 cells and MRSA killing. These activities were further enhanced by the PPARα agonist, WY 14643, while abolished by the antagonist, GW6471, in THP-1-ACE cells. Thus, PPARα is an indispensable molecule in ACE-dependent functional upregulation of macrophages in both mice and humans. Competing Interests: Conflict of Interest The authors have declared that no conflict of interest exists.
Databáze:	MEDLINE
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