Eosinophils subvert host resistance to an intracellular pathogen by instigating non-protective IL-4 in CCR2−/− mice

Abstract

Eosinophils contribute to type II immune responses in helminth infections and allergic diseases, however, their influence on intracellular pathogens is less clear. We previously reported that CCR2−/− mice exposed to the intracellular fungal pathogen Histoplasma capsulatum exhibit dampened immunity caused by an early exaggerated IL-4 response. We sought to identify the cellular source promulgating interleukin (IL)-4 in infected mutant animals. Eosinophils were the principal instigators of non-protective IL-4 and depleting this granulocyte population improved fungal clearance in CCR2−/− animals. The deleterious impact of eosinophilia on mycosis was also recapitulated in transgenic animals overexpressing eosinophils. Mechanistic examination of IL-4 induction revealed that phagocytosis of H. capsulatum via the pattern recognition receptor complement receptor (CR) 3 triggered the heightened IL-4 response in murine eosinophils. This phenomenon was conserved in human eosinophils; exposure of cells to the fungal pathogen elicited a robust IL-4 response. Thus, our findings elucidate a detrimental attribute of eosinophil biology in fungal infections that could potentially trigger a collapse in host defenses by instigating type II immunity.

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“…IL-4 and IFN-γ are important cytokines with regulatory effects on immune cells such as B lymphocytes, T lymphocytes, and macrophages, which can trigger humoral and cellular immune responses. , The secretion of IL-4 cytokine promotes the Th2-polarized immune response, while the increased IFN-γ secretion boosts the Th1-polarized immune response . Therefore, the secretion of IL-4 and IFN-γ was detected and analyzed through the enzyme-linked immunosorbent spot (ELISPOT) assay.…”