Abstract
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.
Highlights
The opportunistic fungal pathogen Candida albicans has emerged as a significant cause of morbidity and mortality worldwide, in immunocompromised individuals [1]
IL-17 can promote neutrophil trafficking in some situations, we recently showed in a mouse model that this is not the case during oropharyngeal candidiasis (OPC)
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 (GCSF), a key trigger of emergency granulopoiesis
Summary
The opportunistic fungal pathogen Candida albicans has emerged as a significant cause of morbidity and mortality worldwide, in immunocompromised individuals [1]. Of the diverse forms of disease manifestations, mucosal infections with C. albicans are by far most abundant [2]. With the everincreasing population of immunocompromised patients, C. albicans infections represent an important socio-economic challenge worldwide. By producing inflammatory mediators and antifungal defense molecules the epithelium actively participates in the host response and together with leukocytes, including neutrophils and IL-17-producing lymphocytes, contributes to limiting fungal (over)growth. Diverse mutual interactions between leukocytes and the epithelium are critical for mounting a broadly protective response against C. albicans. Neutrophils have been shown to rapidly accumulate in the oral mucosa in response to C. albicans infection, and they critically contribute to prevent invasion of the fungus in underlying tissues and dissemination to the circulation and visceral organs as was shown in a model of acute oropharyngeal candidiasis (OPC) [6,7]. The relevance of neutrophils in protection from oropharyngeal candidiasis is evidenced by the high incidence of the disease in hemato-oncological patients with bone marrow aplasia [8,9]
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