Gas6/TAM signaling differentially modulates chronic fungal asthma with the expansion of myeloid regulatory cell subsets in mice (57.7)

Abstract

Abstract Gas6, a Tyro3, Axl, Mertk (TAM) receptor ligand, is detected in a variety of diseases and has various roles. Herein, we show that Gas6 differentially modulates experimental fungal asthmatic response via the expansion and modulation of myeloid-derived regulatory cells (MDRCs). Aspergillus fumigatus-sensitized mice were challenged with live Aspergillus conidia and received approximately 2 μg (low) or 7 μg (high) of recombinant Gas6 via intranasal installation from days 14 to 28 after conidia challenge. In the low dose Gas6 group, significant airway hyperresponsiveness (AHR), airway remodeling, and whole lung IL-13 were observed compared with the control group. Although high dose Gas6 treatment significantly suppressed AHR and the whole lung levels of inflammatory cytokines compared with control, this treatment exacerbated airway remodeling. MDRCs have both disease enhancing and suppressing cells in asthma. Indeed, low dose Gas6 treatment increased the accumulation of CD11b+F4/80+Ly6C-Ly6G+ MDRC with pro-inflammatory properties into asthmatic lung whereas high dose Gas6 promoted the accumulation of immunosuppressive CD11b+F4/80+Ly6C+Ly6G- MDRC during chronic asthma. Anti-Axl Ab, but not anti-Mer Ab, treatment significantly suppressed not only AHR but also airway remodeling in asthmatic mice compared with IgG control asthmatic groups. Together, these results demonstrate that Gas6-TAM receptor interactions modulate fungal asthma, in part through effects on MDRCs.