Activation of neutrophils by autocrine IL-17A–IL-17RC interactions during fungal infection is regulated by IL-6, IL-23, RORγt and dectin-2

Abstract

Here we identified a population of bone marrow neutrophils that constitutively express RORγt and which can produce and respond to IL-17A (IL-17). IL-6, IL-23 and RORγt, but not T cells or NK cells, are required for IL-17 production in neutrophils. IL-6 and IL-23 induced IL-17RC and Dectin-2 expression in neutrophils, and expression of IL-17RC was augmented by Aspergillus and Dectin-2 activation. Autocrine IL-17A–IL-17 receptor activity induced production of reactive oxygen species (ROS), and increased fungal killing in vitro and in a model of Aspergillus keratitis. Human neutrophils also expressed RORγt, and induced IL-17A, IL-17RC and Dectin-2 expression following IL-6 and IL-23 stimulation. These findings identify a population of human and murine neutrophils that exhibit autocrine IL-17 activity, and which likely contribute to the etiology of microbial and inflammatory diseases.

IL-1 signaling inhibits Trichophyton rubrum conidia development and modulates the IL-17 response in vivo

“…33 Even neutrophils can be a source of IL-17, 35 and their importance in a model of keratitis by Aspergillus was also documented. 36 In conclusion, our findings add T.rubrum as another NLRP3 inflammasome activator, supporting this system as another component of the inflammatory process in dermatophytosis. Also, we showed a remarkable role for IL-1 signaling in the shaping of the response of macrophages to this pathogen and in IL-17 response in vivo.…”

The roles and functional mechanisms of interleukin-17 family cytokines in mucosal immunity

“…A population of neutrophils constitutively expresses the transcription factor RORγt to produce IL-17 in response to IL-6 and IL-23. 81 These neutrophils also respond to self-secreted IL-17 to produce reactive oxygen species (ROS) for fungal killing. 81 In addition to extracellular bacteria and fungi, IL-17 also indirectly protects mice from intracellular bacterial infection.…”

“…81 These neutrophils also respond to self-secreted IL-17 to produce reactive oxygen species (ROS) for fungal killing. 81 In addition to extracellular bacteria and fungi, IL-17 also indirectly protects mice from intracellular bacterial infection. During Francisella tularensis infection, IL-17 may induce IL-12 production from myeloid cells to promote a Th1 response.…”

T cell mediated pathogenesis in EAE: Molecular mechanisms

“…[60] Furthermore, IL-17 was shown to be also expressed by mast cells [61] and neutrophils. [62][63][64] IL-7A/F acts mostly on the tissue cells by signaling via the heterodimeric IL-17 receptor composed of IL-17RA [65] and IL-17RC. [66,67] The action of IL-17 is manifold, as it was shown to induce the secretion of matrix metalloproteases (MMP1, MMP3, MMP9, MMP12, and MMP13) and cytokines like GM-CSF, IL-6, and a bunch of chemokines (CCL2, CCL7, CCL20, CXCL1, CXCL2, and CXCL5) by local tissue cells.…”