We recently showed that IL-13 or peroxisome proliferator activated receptor γ (PPARγ) ligands attenuate Candida albicans colonization of the gastrointestinal tract. Here, using a macrophage-specific Dectin-1 deficient mice model, we demonstrate that Dectin-1 is essential to control fungal gastrointestinal infection by PPARγ ligands. We also show that the phagocytosis of yeast and the release of reactive oxygen intermediates in response to Candida albicans challenge are impaired in macrophages from Dectin-1 deficient mice treated with PPARγ ligands or IL-13. Although the Mannose Receptor is not sufficient to trigger antifungal functions during the alternative activation of macrophages, our data establish the involvement of the Mannose Receptor in the initial recognition of non-opsonized Candida albicans by macrophages. We also demonstrate for the first time that the modulation of Dectin-1 expression by IL-13 involves the PPARγ signaling pathway. These findings are consistent with a crucial role for PPARγ in the alternative activation of macrophages by Th2 cytokines. Altogether these data suggest that PPARγ ligands may be of therapeutic value in esophageal and gastrointestinal candidiasis in patients severely immunocompromised or with metabolic diseases in whom the prevalence of candidiasis is considerable. Since the early 1980s, Candida albicans has emerged as major cause of human disease, especially among immunocompromised individuals and those with metabolic dysfunction. The main host defense mechanisms against this yeast are engulfment and the production of reactive oxygen molecules by macrophages through Dectin-1 and the Mannose Receptor, two macrophage receptors for Candida albicans cell wall sugars. However, the contribution of these two receptors remains unclear. In our animal experiments, the lack of Dectin-1 in macrophages renders the animals more susceptible to gastrointestinal infection with Candida albicans, demonstrating the essential role of Dectin-1 in antifungal defense. In addition, our experiments established that the interaction between Dectin-1 and Mannose Receptor is important to orchestrate the host antifungal defense. Thus, Candida albicans clearance would be improved by Dectin-1 and Mannose Receptor up-regulation. Interestingly, we had established that the expression of these two receptors was increased by IL-13 through the activation of the nuclear receptor PPARγ, suggesting that PPARγ could be a therapeutic target to eliminate fungal infection. This paper, which highlights a new area of application of PPARγ ligands in infectious diseases, hence heralds the emergence of a new therapeutic strategy against fungal infection in severely immunocompromised patients or those with metabolic diseases.

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-α^high, IL-10^high, MR, Dectin-1). Interestingly, rosiglitazone induces a phenotypic M2b-to-M2a (TNF-α^low, IL-10^low, MR^high, Dectin-1^high) 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.

CD36 is the major receptor mediating nonopsonic phagocytosis of Plasmodium falciparum-parasitized erythrocytes by macrophages. Its expression on macrophages is mainly controlled by the nuclear receptor PPARγ. Here, we demonstrate that inflammatory processes negatively regulate CD36 expression on human and murine macrophages, and hence decrease Plasmodium clearance directly favoring the worsening of malaria infection. This CD36 downregulation in inflammatory conditions is associated with a failure in the expression and activation of PPARγ. Interestingly, using siRNA mediating knock down of Nrf2 in macrophages or Nrf2- and PPARγ-deficient macrophages, we establish that in inflammatory conditions, the Nrf2 transcription factor controls CD36 expression independently of PPARγ. In these conditions, Nrf2 activators, but not PPARγ ligands, enhance CD36 expression and CD36-mediated Plasmodium phagocytosis. These results were confirmed in human macrophages and in vivo where only Nrf2 activators improve the outcome of severe malaria. Collectively, this report highlights that the Nrf2 transcription factor could be an alternative target to PPARγ in the control of severe malaria through parasite clearance. Severe and fatal malaria is still increasing both in incidence and in its resistance to antimalarial agents. The improved understanding of immune mechanisms mediating Plasmodium elimination might therefore offer a complementary way to conventional therapeutic interventions. The main host innate immune defense mechanism against Plasmodium falciparum is the engulfment by macrophages through CD36, the macrophage receptor recognizing infected erythrocytes. The up-regulation of CD36 on macrophages therefore represents an alternative way to favor parasite clearance during infection. Severe malaria infection is associated with an excessive production of proinflammatory markers and an inability to control parasite proliferation. We demonstrate here that malaria-induced inflammation down regulates CD36 expression on macrophages and favors the worsening of malaria infection. The conventional way to promote CD36 expression through PPARγ nuclear receptor is inefficient under malaria inflammatory processes. Interestingly, we establish that the Nrf2 transcription factor may substitute PPARγ to promote CD36 expression and its associated functions in inflammatory conditions. As a consequence, only Nrf2 but not PPARγ activators improve the outcome of severe malaria in vivo. This paper which highlights a new area of application for Nrf2 activators in infectious diseases, heralds the emergence of a new therapeutic strategy against severe malaria.

Liver receptor homologue-1 (LRH-1) is a nuclear receptor involved in the repression of inflammatory processes in the hepatointestinal tract. Here we report that LRH-1 is expressed in macrophages and induced by the Th2 cytokine IL-13 via a mechanism involving STAT6. We show that loss-of-function of LRH-1 in macrophages impedes IL-13-induced macrophage polarization due to impaired generation of 15-HETE PPARγ ligands. The incapacity to generate 15-HETE metabolites is at least partially caused by the compromised regulation of CYP1A1 and CYP1B1. Mice with LRH-1-deficient macrophages are, furthermore, highly susceptible to gastrointestinal and systemic Candida albicans infection. Altogether, these results identify LRH-1 as a critical component of the anti-inflammatory and fungicidal response of alternatively activated macrophages that acts upstream from the IL-13-induced 15-HETE/PPARγ axis.