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.

Adult human subcutaneous adipose tissue (AT) harbors a rich population of mesenchymal stromal cells (MSCs) that are of interest for tissue repair. For this purpose, it is of utmost importance to determine the response of AT-MSCs to proliferative and inflammatory signals within the damaged tissue. We have characterized the transcriptional profile of cytokines, regulatory mediators and Toll-like receptors (TLR) relevant to the response of MSCs. AT-MSCs constitutively present a distinct profile for each gene and differentially responded to inflammation and cell-passaging. Inflammation leads to an upregulation of IL-6, IL-8, IL-1β, TNFα and CCL5 cytokine expression. Inflammation and cell-passaging increased the expression of HGF, IDO1, PTGS1, PTGS2 and TGFβ. The expression of the TLR pattern was differentially modulated with TLR 1, 2, 3, 4, 9 and 10 being increased, whereas TLR 5 and 6 downregulated. Functional enrichment analysis demonstrated a complex interplay between cytokines, TLR and regulatory mediators central for tissue repair. This profiling highlights that following a combination of inflammatory and proliferative signals, the sensitivity and responsive capacity of AT-MSCs may be significantly modified. Understanding these transcriptional changes may help the development of novel therapeutic approaches.

In this research, we induced acute kidney injury (AKI) by ischemia-reperfusion injury (IRI), one of its main causes. Then, we assessed kidney dysfunction by CRE (creatinine)/BUN (serum blood urea nitrogen) levels and histological analysis. Surprisingly, kidney macrophages, initially not expressing MafB and c-Maf, expressed both of them 48 h after bilateral ischemia renal disease (double IRD; dIRD), supporting their possible roles in the disease. We speculated that the M2 macrophages involved in AKI repair might be the source of MafB and c-Maf after injury and that these two transcription factors could have a significant role in the disease. Considering that IL-4/IL-13-induced M2a is the main contributor to AKI recovery and that MafB is upregulated under the effect of these two cytokines combined, we chose to focus on MafB analysis and aimed to examine its potential role in IRD. Previous studies have not examined the role of MafB in ischemic renal disease (IRD). In this study, we demonstrated a significant loss of brush borders, accumulation of intraluminal debris, and extensive damage to the anatomical structure of the MafB^f/f::Lys-Cre mice kidneys compared to their littermates, MafB^f/f, which are considered as a negative control in the entire paper. This was marked by the enlarged tubules, a significant decrease in mature macrophages (F4/80⁺ cells), and, therefore, worsening of the disease in the absence of MafB and delay/failure of the early signs of ischemia recovery. Importantly, these MafB cKO mice presented higher mortality, caused by the abrogation of the intraluminal debris clearance, and died after 48 h from IRD, suggesting the involvement of MafB in the signaling pathway of this pathology. Therefore, we found evidence that MafB attenuates IRD.