Mucosal infections with Candida albicans belong to the most frequent forms of fungal diseases. Host protection is conferred by cellular immunity; however, the induction of antifungal immunity is not well understood. Using a mouse model of oropharyngeal candidiasis (OPC) we show that interleukin-1 receptor (IL-1R) signaling is critical for fungal control at the onset of infection through its impact on neutrophils at two levels. We demonstrate that both the recruitment of circulating neutrophils to the site of infection and the mobilization of newly generated neutrophils from the bone marrow depended on IL-1R. Consistently, IL-1R-deficient mice displayed impaired chemokine production at the site of infection and defective secretion of granulocyte colony-stimulating factor (G-CSF) in the circulation in response to C. albicans. Strikingly, endothelial cells were identified as the primary cellular source of G-CSF during OPC, which responded to IL-1α that was released from keratinocytes in the infected tissue. The IL-1-dependent crosstalk between two different cellular subsets of the nonhematopoietic compartment was confirmed in vitro using a novel murine tongue-derived keratinocyte cell line and an established endothelial cell line. These data establish a new link between IL-1 and granulopoiesis in the context of fungal infection. Together, we identified two complementary mechanisms coordinating the neutrophil response in the oral mucosa, which is critical for preventing fungal growth and dissemination, and thus protects the host from disease. The opportunistic pathogen Candida albicans is a major risk factor for immunosuppressed individuals, and oropharyngeal candidiasis (OPC) is a frequent complication in patients with weakened cellular immunity. The cytokine interleukin-17 (IL-17) plays a critical role for antifungal host defense and was proposed to act by regulating neutrophil recruitment to the oral mucosa. However, although IL-17 can promote neutrophil trafficking in some situations, we recently showed in a mouse model that this is not the case during OPC. Thus, the mechanism governing the neutrophil response to C. albicans remained to be determined. Here, we demonstrate an essential role of IL-1 receptor (IL-1R) signaling in the recruitment of neutrophils from the circulation to the infected tissue via enhanced secretion of chemokines and increased output of neutrophils from the bone marrow. We found that IL-1α is released from keratinocytes upon invasion of C. albicans and acts on endothelial cells to induce the production of granulocyte colony-stimulating factor (G-CSF), a key trigger of emergency granulopoiesis. Thereby, IL-1R signaling translates the local response to the fungus in the oral mucosa into a systemic response that critically contributes to protection from infection.

The skin of mammalian organisms is home for a myriad of microbes. Many of these commensals are thought to have beneficial effects on the host by critically contributing to immune homeostasis. Consequently, dysbiosis can have detrimental effects for the host that may manifest with inflammatory diseases at the barrier tissue. Besides bacteria, fungi make an important contribution to the microbiota and among these, the yeast Malassezia widely dominates in most areas of the skin in healthy individuals. There is accumulating evidence that Malassezia spp. are involved in a variety of skin disorders in humans ranging from non- or mildly inflammatory conditions such as dandruff and pityriasis versicolor to more severe inflammatory skin diseases like seborrheic eczema and atopic dermatitis. In addition, Malassezia is strongly linked to the development of dermatitis and otitis externa in dogs. However, the association of Malassezia spp. with such diseases remains poorly characterized. Until now, studies on the fungus–host interaction remain sparse and they are mostly limited to experiments with isolated host cells in vitro. They suggest a multifaceted crosstalk of Malassezia spp. with the skin by direct activation of the host via conserved pattern recognition receptors and indirectly via the release of fungus-derived metabolites that can modulate the function of hematopoietic and/or non-hematopoietic cells in the barrier tissue. In this review, we discuss our current understanding of the host response to Malassezia spp. in the mammalian skin.

The field of IL-17 biology has received much attention over the last decade owing to the pathogenic role of this cytokine in psoriasis and other autoinflammatory disorders and the successful implementation of IL-17-targeting therapies in patients suffering from these diseases. IL-17-mediated pathologies are contrasted by the important host beneficial effects of this cytokine. IL-17 is essential for regulating microbial colonization in barrier tissues. Rare congenital defects in the IL-17 pathway exemplify the relevance of IL-17 in protective immunity against the opportunistic fungal pathogen C. albicans. However, more recently, evidence is accumulating that IL-17 can also provide protection against fungi other than C. albicans. Importantly, protective IL-17 responses directed against commensal fungi can, under certain conditions, promote inflammation with detrimental consequences for the host, thereby assigning fungi a new role as disease-promoting factors apart from their role as potential infectious agents.