Loss of MafA and MafB expression promotes islet inflammation

Abstract

Maf transcription factors are critical regulators of beta-cell function. We have previously shown that reduced MafA expression in human and mouse islets is associated with a pro-inflammatory gene signature. Here, we investigate if the loss of Maf transcription factors induced autoimmune processes in the pancreas. Transcriptomics analysis showed expression of pro-inflammatory as well as immune cell marker genes. However, clusters of CD4+ T and B220+ B cells were associated primarily with adult MafA −/− MafB +/− , but not MafA −/− islets. MafA expression was detected in the thymus, lymph nodes and bone marrow suggesting a novel role of MafA in regulating immune-cell function. Analysis of pancreatic lymph node cells showed activation of CD4+ T cells, but lack of CD8+ T cell activation which also coincided with an enrichment of naïve CD8+ T cells. Further analysis of T cell marker genes revealed a reduction of T cell receptor signaling gene expression in CD8, but not in CD4+ T cells, which was accompanied with a defect in early T cell receptor signaling in mutant CD8+ T cells. These results suggest that loss of MafA impairs both beta- and T cell function affecting the balance of peripheral immune responses against islet autoantigens, resulting in local inflammation in pancreatic islets.

An Inducible Diabetes Mellitus Murine Model Based on MafB Conditional Knockout under MafA-Deficient Condition

“…In this study, we did not detect obvious immune cell infiltration in the pancreatic tissues of male A0B Δpanc mice. However—different from our results—according to Singh et al [ 37 ], loss of Mafa and Mafb expression promotes inflammation of the pancreatic islets. This may be explained by the following two reasons: First, the mice models used by Singh et al [ 37 ] were Mafa −/− and Mafb +/− mice, which were whole body knockouts, while the mice used by us were Maf −/− ; Mafb flox/flox , and Pdx1-CreER TM .…”

“…Second, the feeding time may also affect the occurrence of some histological changes. Singh et al [ 37 ] kept the mice for 6–8 months, 2-4 months longer than ours. Collectively, owing to the different genotypes and feeding times, the phenotype may be explainable.…”

miR-155 Knockdown Protects against Cerebral Ischemia and Reperfusion Injury by Targeting MafB

“…In hepatic ischemia-reperfusion, the lack of miR-155 can upregulate SOCS-1 expression and reduce the hepatic damage [11]. Maf is a family described as transcriptional activators and MafB plays a crucial part in mediating the inflammatory reaction in immune cells [19]. e results of our study revealed that miR-155 was upregulated while MafB was downregulated in patients with CIRI and CIR cell models in vitro and mouse models in vivo.…”

“…MafB is a kind of the large musculoaponeurotic fibrosarcoma oncogene (Maf ) family proteins with a basic leucine zipper structure, which acts as a critical transcriptional activator of anti-inflammatory cytokine genes [19]. Considering information about the underlying mechanism of miR-155 in CIR injury is rarely known, we conducted this research to examine the expression of miR-155 and MafB and their relationship in patients with cerebral ischemiareperfusion injury (CIRI), exploring their biological functions and molecular mechanism in oxygen glucose deprivation/reoxygenation (OGD/R) induced SH-SY5Y cells in vitro, as well as in the mouse models with middle cerebral artery occlusion (MCAO) in vivo.…”

The MafA-target gene PPP1R1A regulates GLP1R-mediated amplification of glucose-stimulated insulin secretion in β-cells

“…MafA floxed (MafA fl/fl ) mice were crossed with Sox2-Cre or RIP-Cre mice to obtain total MafA [22] or β-cell-specific [23] MafA deletion. Mice were maintained on C57BL/6 background and housed in colony cages (3-5/cage) in a 12h light/dark cycle with controlled humidity and temperature and free access to standard diet and water.…”