Macrophage mannose receptor (MMR) is an important component of the innate immune system implicated in host defense against microbial infections such as candidiasis and in antigen presentation. We demonstrate here that the MMR expression is induced in mouse peritoneal macrophages following exposure to PPARgamma ligands or to interleukine-13 (IL-13) via a PPARgamma signaling pathway. Ligand activation of the PPARgamma in macrophages promotes uptake, killing of Candida albicans, and reactive oxygen intermediates production triggered by the yeasts through MMR overexpression. We also show that MMR induction by IL-13 via PPARgamma is dependent on phopholipase A2 activation and that IL-13 induces 15d-PGJ2 production and nuclear localization. These results reveal a novel signaling pathway controlling the MMR surface expression and suggest that endogenous PPARgamma ligand produced by phospholipase A2 activation may be an important regulator of MMR expression by IL-13.

The class B scavenger receptor CD36 is a component of the pattern recognition receptors on monocytes that recognizes a variety of molecules. CD36 expression in monocytes depends on exposure to soluble mediators. We demonstrate here that CD36 expression is induced in human monocytes following exposure to IL-13, a Th2 cytokine, via the peroxisome proliferator-activated receptor (PPAR)c pathway. Induction of CD36 protein was paralleled by an increase in CD36 mRNA. The PPARc pathway was demonstrated using transfection of a PPARc expression plasmid into the murine macrophage cell line RAW264.7, expressing very low levels of PPARc, and in peritoneal macrophages from PPARc-conditional null mice. We also show that CD36 induction by IL-13 via PPARc is dependent on phospholipase A2 activation and that IL-13 induces the production of endogenous 15-deoxy-D 12,14 -prostaglandin J 2 , an endogenous PPARc ligand, and its nuclear localization in human monocytes. Finally, we demonstrate that CD36 and PPARc are involved in IL-13-mediated phagocytosis of Plasmodium falciparum-parasitized erythrocytes. These results reveal a novel role for PPARc in the alternative activation of monocytes by IL-13, suggesting that endogenous PPARc ligands, produced by phospholipase A2 activation, could contribute to the biochemical and cellular functions of CD36.Leukocyte signaling * These 2 authors contributed equally to this work. IntroductionThe innate immune system protects the host in the early phase of infection. Circulating monocytes and tissue macrophages (Mu) mediate much of this innate immune response [1]. The strategy of recognition in the innate response is mediated by the coordinated action of pathogen-associated molecular patterns and pattern recognition receptors. Scavenger receptors and mannose receptor are important pattern recognition receptors in monocytes/Mu [2,3]. The modulation of the expression of these receptors may be critical in the role of these cells in antigen processing, scavenging, and host defence against pathogens. Several members of the scavenger receptor family, including Mu class A scavenger receptors and CD36, have been identified as receptors for modified lipoproteins on Mu, and their relevance to lipid uptake has been demonstrated in vitro and in vivo [4]. The scavenger receptor CD36, an 88-kDa integral membrane protein, is a class B scavenger receptor expressed on a wide variety of cells, in particular on monocytes and monocytederived Mu [5,6]. CD36 is known as a receptor for the uptake of oxidatively modified low-density lipoprotein (LDL) [7] and is also able to bind anionic phospholipid phosphatidylserine [8]. This scavenger receptor is implicated in the clearance of apoptotic cells [9]. Recently, McGilvray and colleagues [10] described a CD36-dependent nonopsonic phagocytosis of erythrocytes containing P. falciparum, by monocytes and culture-derived Mu, and a decrease in the parasiteinduced TNF secretion by monocytes/Mu. These processes were accentuated by CD36 up-regulation by peroxisome proliferator-acti...

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In chronic inflammatory diseases, such as rheumatoid arthritis, inflammation acts as an independent cardiovascular risk factor and the use of anti-inflammatory drugs, such as anti-tumor necrosis factor alpha (anti-TNFα), may decrease this risk. The phagocytosis of oxidized low density lipoproteins (LDLs) accumulated in the subendothelium by mononuclear cells influences atherosclerosis and depends on CD36 expression. We investigated the role of TNFα and adalimumab, a human anti-TNFα monoclonal antibody widely used in human pathology, in CD36 expression in human monocytes. Human monocytes were prepared by adherence from whole-blood buffy-coat fractions from healthy donors. CD36 expression was assessed by RT-PCR and flow cytometry, with various TNFα or adalimumab concentrations. Implication of peroxisome proliferator-activated receptor (PPAR)γ in the regulation of CD36 expression was assessed using specific inhibitor or gel shift assays. The impact of redox signaling was investigated using quantification of reactive oxygen species, antioxidant and a NADPH oxidase inhibitor. The F(ab')2 fragment of adalimumab was isolated and its effect was analyzed. TNFα inhibits both CD36 membrane expression and mRNA expression. This inhibition involves a reduction in PPARγ activation. In contrast, adalimumab increases both CD36 membrane expression and mRNA expression. This induction is independent of the Fc portion of adalimumab and involves redox signaling via NADPH oxidase activation. CD36 expression on human monocytes is inhibited by TNFα and independently increased by adalimumab. These data highlight that pro-inflammatory cytokines and their specific neutralization influence the expression of cellular receptors implicated in atherosclerosis. Further studies are needed to investigate the clinical implications of these results in accelerated atherosclerosis observed in rheumatoid arthritis.

We recently demonstrated that in vitro peroxisome proliferator-activated receptor-γ (PPARγ) activation of mouse peritoneal macrophages by IL-13 or PPARγ ligands promotes uptake and killing of Candida albicans through mannose receptor overexpression. In this study, we demonstrate that i.p. treatment of immunocompetent and immunodeficient (RAG-2−/−) mice with natural and synthetic PPARγ-specific ligands or with IL-13 decreases C. albicans colonization of the gastrointestinal (GI) tract 8 days following oral infection with the yeast. We also showed that Candida GI infection triggers macrophage recruitment in cecum mucosa. These mucosal macrophages, as well as peritoneal macrophages, overexpress the mannose receptor after IL-13 and rosiglitazone treatments. The treatments promote macrophage activation against C. albicans as suggested by the increased ability of peritoneal macrophages to phagocyte C. albicans and to produce reactive oxygen intermediates after yeast challenge. These effects on C. albicans GI infection and on macrophage activation are suppressed by treatment of mice with GW9662, a selective PPARγ antagonist, and are reduced in PPARγ+/− mice. Overall, these data demonstrate that IL-13 or PPARγ ligands attenuate C. albicans infection of the GI tract through PPARγ activation and hence suggest that PPARγ ligands may be of therapeutic value in esophageal and GI candidiasis in immunocompromised patients.

Macrophage-mediated cytotoxicity is controlled by surface receptor expression and activation. Despite the numerous studies documenting the role of macrophage C-type lectin receptors (CLR) in pathogen elimination, little is known about their contribution to antitumor responses. Here, we report that IL13 inhibits T-cell lymphoma and ovarian adenocarcinoma development in tumor-bearing mice through the conversion of tumor-supporting macrophages to cytotoxic effectors, characterized by a CLR signature composed of dectin-1 and mannose receptor (MR). We show that dectin-1 and MR are critical for the recognition of tumor cells through sialic acid-specific glycan structure on their surface and for the subsequent activation of macrophage tumoricidal response. Finally, we validated that IL13 antitumor effect mediated by dectin-1 and MR overexpression on macrophages can extend to various types of human tumors. Therefore, these results identify these CLRs as potential targets to promote macrophage antitumor response and represent an attractive approach to elicit tumor-associated macrophage tumoricidal properties.

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The aim of this randomized prospective study was to assess the efficacy and safety of a triple therapy with interferon-alpha (IFN-alpha)-ribavirin-interleukin-2 (IL-2) for the treatment of patients with genotype 1 infection and high viral load nonresponsive to primary IFN-ribavirin therapy. Twenty hepatitis C virus (HCV) genotype 1 patients with high viral load and Metavir fibrosis score >or=2 without HIV co-infection who were previously nonviral responders to standard treatment with IFN plus ribavirin were intensively re-treated with IFN-alpha2a (3 millions (M) IU every 2 days) combined with ribavirin (1000-1200 mg/day) for a 24-week period. Patients were randomized to receive four cycles of subcutaneous injection of IL-2 (3 MIU/day, 5 days a week every 3 weeks) during either the first 12 weeks (group 1, n = 10) or the last 12 weeks (group 2, n = 10) of combination therapy. At the end of triple therapy, six patients (30%) achieved a biochemical response and 4 (20%) a viral response followed by a relapse after triple therapy withdrawal. After 12 weeks of therapy, no difference in viral load was observed between the groups. The decrease in viral load in group 2 was not raised after the addition of IL-2 to IFN plus ribavirin combination therapy. No serious adverse effects were observed. In conclusion, in patients with poor predictive factors of response, the addition of IL-2 to IFN ribavirin combination therapy does not exert a favourable impact on HCV treatment.