Abstract
Obesity is associated with a chronic low-grade inflammation that predisposes to insulin resistance and the development of type 2 diabetes. In this metabolic context, gastrointestinal (GI) candidiasis is common. We recently demonstrated that the PPARγ ligand rosiglitazone promotes the clearance of Candida albicans through the activation of alternative M2 macrophage polarization. Here, we evaluated the impact of high fat diet (HFD)-induced obesity and the effect of rosiglitazone (PPARγ ligand) or WY14643 (PPARα ligand) both on the phenotypic M1/M2 polarization of peritoneal and cecal tissue macrophages and on the outcome of GI candidiasis. We demonstrated that the peritoneal macrophages and the cell types present in the cecal tissue from HF fed mice present a M2b polarization (TNF-αhigh, IL-10high, MR, Dectin-1). Interestingly, rosiglitazone induces a phenotypic M2b-to-M2a (TNF-αlow, IL-10low, MRhigh, Dectin-1high) switch of peritoneal macrophages and of the cells present in the cecal tissue. The incapacity of WY14643 to switch this polarization toward M2a state, strongly suggests the specific involvement of PPARγ in this mechanism. We showed that in insulin resistant mice, M2b polarization of macrophages present on the site of infection is associated with an increased susceptibility to GI candidiasis, whereas M2a polarization after rosiglitazone treatment favours the GI fungal elimination independently of reduced blood glucose. In conclusion, our data demonstrate a dual benefit of PPARγ ligands because they promote mucosal defence mechanisms against GI candidiasis through M2a macrophage polarization while regulating blood glucose level.
Highlights
Obesity is associated with a chronic low-grade inflammation that predisposes to insulin resistance and development of type 2 diabetes
We previously reported that IL-13, a Th2 cytokine, promotes in vitro and in vivo the elimination of C. albicans by increasing the expression at the surface of macrophages of Mannose Receptor (MR) and Dectin-1, Ctype lectin receptors involved in non-opsonized C.albicans recognition and phagocytosis and in the production of reactive oxygen species [13,14,15]
We evaluated the impact of insulin resistance induced by high fat diet (HFD) and the effect of rosiglitazone (PPARc ligand) or WY14643 (PPARa ligand) on the phenotypic differentiation of peritoneal macrophages and of the cell types present in the cecal tissue
Summary
Obesity is associated with a chronic low-grade inflammation that predisposes to insulin resistance and development of type 2 diabetes. A recent report proposed that the chronic inflammatory alterations during fat mass development are associated with increased abundance of macrophages in adipose tissue which present a particular M2 remodelling phenotype These macrophages resembled M2 macrophages phenotypically by surface expression of Mannose Receptor (MR), CD163 and integrin avb, their endocytic activity and production of anti-inflammatory cytokines (IL-10, IL-1Ra), but represent an unique type of macrophages that secrete large amounts of pro-inflammatory cytokines. We determined that IFNc, a Th1 cytokine, inhibits the non-opsonized C.albicans phagocytosis by decreasing C-type lectin receptor expression on macrophage surface, but eliminates yeast by increasing the expression of opsonized receptors at the surface of macrophages and the macrophage inflammatory properties [16] All these data clearly demonstrate the complementarities of these 2 types of macrophage polarization in the elimination of fungal infection. These findings demonstrate in a hyperglycaemic metabolic context a dual benefit of PPARc ligands, which are able to regulate blood glucose level and strengthen M2a defence of macrophages during fungal infections
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