c-MAF dependent perivascular macrophages regulate diet induced metabolic syndrome

Abstract

Macrophages are an essential part of tissue development and physiology. Perivascular macrophages have been described in tissues and appear to play a role in development and disease processes, although it remains unclear what are the key features of these cells. Here, we identify a subpopulation of perivascular macrophages in several organs, characterized by their dependence on the transcription factor c-MAF, displaying non-conventional macrophage markers including LYVE1, Folate receptor 2 and CD38. Conditional deletion of c-MAF in macrophage lineages caused ablation of perivascular macrophages in the brain and altered muscularis macrophages program in the intestine. In the white adipose tissue (WAT), c-MAF deficient perivascular macrophages displayed an altered gene expression profile, which was linked to an increased vascular branching into the tissue. Upon feeding on high fat diet (HFD), mice with c-MAF deficient macrophages showed improved metabolic parameters compared to wild-type mice, including less weight gain, greater glucose tolerance and reduced inflammatory cell profile in WAT. These results define c-MAF as a central regulator of perivascular macrophages cell identity and transcriptional program in vivo and reveal a novel role for this tissue resident macrophage population in the regulation of metabolic syndrome.

Microbial Energy Metabolism Fuels a CSF2-dependent Intestinal Macrophage Niche within Tertiary Lymphoid Organs

“…MPs in clusters 0 and 5 co-expressed Cd4 but not Ccr2, consistent with our flow cytometric classification (Fig 5F). Interestingly, MPs in cluster 5, enriched in the TLO, expressed higher levels of Folr2, which was shown to be expressed in gut and brain c-MAF-dependent perivascular MPs involved in metabolic regulation (Moura Silva et al, 2021). Consistent with previous reports, pathway analysis demonstrated that MPs in clusters 0 and 5 were enriched in endocytosis and vesiclemediated transport pathways and mediated tissue homeostatic functions, including synapse pruning (Fig 5G,Fig S4E).…”

“…UMAP dimensionality reduction and combined analysis of all 4 groups (LP WT , TLO WT , LP Csf2-/-, TLO Csf2-/-) yielded 18 clusters from a total of 15,369 cells (Fig S4A). Based on their top 30 cluster-defining genes, we identified clusters corresponding to B cells (clusters 7, 10), T/NK cells (cluster 14), and epithelial and stromal cells (clusters 0, 5, 6, 9, 11, 15-17), which were excluded from subsequent analysis ( Moura Silva et al, 2021). MPs in clusters 0 and 5 co-expressed Cd4 but not Ccr2, consistent with our flow cytometric classification (Fig 5F).…”

Perivascular macrophages collaborate to facilitate chemotherapy resistance in cancer

“…However, surprisingly, in homeostatic tissues, tissue resident Lyve-1 + macrophage populations also expressed HO-1. We identified in vitro that c-MAF signaling was required for Lyve-1, HO-1 and CD206 expression on BMDMs in response to IL-6 and could link these markers on tissue resident macrophages in non-inflammed healthy tissues which have recently been demonstrated also to be c-MAF-dependent (44). Although the signal for c-MAF in healthy tissues is unknown, it could explain the unexpected high expression of HO-1 which is generally considered as a stress-or inflammation-inducible enzyme (30,62).…”

“…3F) was most likely directly due to the loss of IL-6 from the TME. Recent data demonstrated that the transcription factor c-MAF was vital to the development of Lyve-1 + Pv macrophages in healthy tissues (44), and we sought to establish whether c-MAF signaling may account for the Lyve-1 + macrophage phenotype observed through IL-6 stimulation. IL-6 signaling is associated with the JAK/STAT3 pathway (45), however, STAT3 has been linked to the expression of c-MAF via the basic leucine zipper transcription factor ATF-like, Batf in T follicular helper cells (46).…”

Perivascular macrophages in theCNS: From health to neurovascular diseases

“…Conditional knockout of c-MAF in macrophage lineages will cause ablation of PVMs in the CNS. 39 MAFB also belongs to the Maf family, with the function of controlling the proliferation rate of PVMs through the epigenetic regulation of self-renewing genes. 40,41 Beyond that, MAFB is also able to limit the ability of macrophage colony-stimulating factor (M-CSF) in differentiating HSCs to PVMs.…”