Abstract
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.
Highlights
Innate immunity is a conserved mechanism of host defense and is responsible for immediately recognizing microbial invasion through the engagement of pattern-recognition receptors (PRRs)
To explore the role of Dectin-1 and the Mannose Receptor (MR) in the control of fungal infection by alternatively activated macrophages (M2), we studied the phagocytosis of non-opsonized C.albicans and the production of yeast-induced reactive oxygen species (ROS) by macrophages, in the presence or absence of soluble receptor blocking agents
Since C.albicans stimulates phagocytosis, and since this function contributes to the triggering of ROS production, we examined the respiratory burst induced by non-opsonized C.albicans in IL-13 polarized macrophages
Summary
Innate immunity is a conserved mechanism of host defense and is responsible for immediately recognizing microbial invasion through the engagement of pattern-recognition receptors (PRRs) These PRRs can recognize highly conserved microbial structures, known as pathogen-associated molecular patterns (PAMPs). The best characterized family of PRRs is the Toll-like receptors (TLRs) originally supposed to mediate cellular signaling, but the membrane-associated C-type lectin receptors have since emerged as major receptors in functions related to pathogen binding, uptake, and killing. They contribute to the initiation and the modulation of the immune response. This type II transmembrane receptor consists of a single CRD involved in the calcium-independent recognition of b-1, 3-glucans exposed on particles such as zymosan, or many fungal species, including Saccharomyces, Pneumocystis, Aspergillus and Candida [3,4,5]
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