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MAFB in Macrophages Regulates Prostaglandin E2-Mediated Lipid Mediator Class Switch through ALOX15 in Ischemic Acute
Maho Kanai1,2, Teppei Nishino1,3, Dhouha Daassi1
1Department of Anatomy and Embryology, Faculty of Medicine, University of Tsukuba, Tsukuba, Japan.
Abstract:
Monocytes and macrophages express the transcription factor MAFB (V-maf musculoaponeurotic fibrosarcoma oncogene homolog B) and protect against ischemic acute kidney injury (AKI). However, the mechanism through which MAFB alleviates AKI in macrophages remains unclear. In this study, we induced AKI in macrophage lineage-specific Mafb-deficient mice (C57BL/6J) using the ischemia-reperfusion injury model to analyze these mechanisms. Our results showed that MAFB regulates the expression of Alox15 (arachidonate 15-lipoxygenase) in macrophages during ischemic AKI. The expression of ALOX15 was significantly decreased at the mRNA and protein levels in macrophages that infiltrated the kidneys of macrophage-specific Mafb-deficient mice at 24 h after ischemia-reperfusion injury. ALOX15 promotes the resolution of inflammation under acute conditions by producing specialized proresolving mediators by oxidizing essential fatty acids. Therefore, MAFB in macrophages promotes the resolution of inflammation in ischemic AKI by regulating the expression of Alox15. Moreover, MAFB expression in macrophages is upregulated via the COX-2/PGE2/EP4 pathway in ischemic AKI. Our in vitro assay showed that MAFB regulates the expression of Alox15 under the COX-2/PGE2/EP4 pathway in macrophages. PGE2 mediates the lipid mediator (LM) class switch from inflammatory LMs to specialized proresolving mediators. Therefore, MAFB plays a key role in the PGE2-mediated LM class switch by regulating the expression of Alox15. Our study identified a previously unknown mechanism by which MAFB in macrophages alleviates ischemic AKI and provides new insights into regulating the LM class switch in acute inflammatory conditions.
Insights
Malignant fibrous histiocytoma (MFH) is a rare soft tissue sarcoma. MAFB transcription factor in macrophages promotes resolution of inflammation in acute kidney injury (AKI) by regulating Alox15 expression and lipid mediator class switching.
Area of Science:
- Immunology
- Molecular Biology
- Nephrology
Background:
- Monocytes and macrophages express MAFB (V-maf musculoaponeurotic fibrosarcoma oncogene homolog B) and protect against ischemic acute kidney injury (AKI).
- The precise mechanism by which MAFB alleviates AKI in macrophages is not fully understood.
- Understanding MAFB's role is crucial for developing novel therapeutic strategies for AKI.
Purpose of the Study:
- To elucidate the mechanism through which MAFB alleviates ischemic AKI in macrophages.
- To investigate the role of MAFB in regulating inflammatory responses and lipid mediator production during AKI.
- To identify potential therapeutic targets for mitigating kidney injury.
Main Methods:
- Induction of AKI in macrophage lineage-specific Mafb-deficient mice using the ischemia-reperfusion injury model.
- Analysis of MAFB and Alox15 (arachidonate 15-lipoxygenase) expression at mRNA and protein levels in infiltrating macrophages.
- In vitro assays to examine the regulation of Alox15 by MAFB under the COX-2/PGE2/EP4 pathway.
Main Results:
- MAFB deficiency in macrophages significantly decreased Alox15 expression during ischemic AKI.
- MAFB regulates Alox15 expression in macrophages via the COX-2/PGE2/EP4 pathway.
- MAFB promotes the resolution of inflammation in ischemic AKI by regulating Alox15 and facilitating the lipid mediator class switch.
Conclusions:
- MAFB in macrophages plays a critical role in alleviating ischemic AKI by regulating Alox15 expression.
- MAFB mediates the PGE2-induced lipid mediator class switch from inflammatory to specialized proresolving mediators.
- This study reveals a novel mechanism for MAFB in macrophage-mediated kidney protection and offers insights into inflammatory resolution pathways.
