IL-1 Coordinates the Neutrophil Response to C. albicans in the Oral Mucosa

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.

Interleukin 1α Is Critical for Resistance against Highly Virulent Aspergillus fumigatus Isolates

“…that were able to undergo hyphal growth induced higher levels of IL-1␣ expression, which were dampened in C. albicans mutants that were defective in hyphal growth (60)(61)(62). Moreover, IL-1␣ plays a critical role in regulating host resistance in murine models of oral candidiasis (63,64). During oral candidiasis, IL-1␣ is secreted by keratinocytes (64).…”

“…This suggests that even in the presence of macrophages, hypervirulent A. fumigatus isolates may continue to grow through either increased nutrient sensing in the phagosome or increased resistance to the antifungal effector functions of macrophages. Similarly, C. albicans drives pyroptosis-dependent and -independent cell death pathways in macrophages, which contributes to the IL-1␤ response from macrophages (63,(73)(74)(75)(76), but its role in IL-1␣ secretion has not been explored. For C. albicans, it is well established that within the macrophage phagosome, the fungi encounter significant nutrient stress, which must be dealt with in order for the fungi to continue to grow and escape the macrophage (77,78).…”

Immunity against fungi

“…Neutrophil recruitment to infected oral tissues is complex, with reports of IL-17-dependent and -independent trafficking pathways (85,86). One IL-17-independent mechanism involves IL-1α/β-sensing oral keratinocytes that regulate neutrophil influx via CXC-chemokine release and indirect control over G-CSF-dependent granulopoiesis (87). Thus, mucosal infections induce crosstalk between epithelial and hematopoietic cells to regulate innate activation and fungal clearance.…”

Control of Mucosal Candidiasis in the Zebrafish Swim Bladder Depends on Neutrophils That Block Filament Invasion and Drive Extracellular-Trap Production

“…To protect from mucosal invasion in OPC, neutrophils must be present in the blood, be recruited to the site of infection, and possess a fully functional antimicrobial arsenal (9)(10)(11)(12). Neutrophils attack both the yeast and filamentous forms of C. albicans and are associated with vulvovaginal candidiasis (13)(14)(15).…”