Soluble gp130 inhibits Th17 polarization in neutrophilic asthma by blocking IL-6-signaling in dendritic cells.

Abstract

Interleukin-6 (IL-6)-signaling modulates immune responses in asthma, yet the mechanisms linking this pathway to Th17 skewing in neutrophilic asthma remain incompletely defined. Here, we evaluated soluble gp130 (sgp130), a selective inhibitor of IL-6-signaling,and. A murine neutrophilic asthma model was established by ovalbumin (OVA) sensitization followed by lipopolysaccharide (LPS) plus OVA challenge, and sgp130 was administered intratracheally. Airway neutrophilic inflammation, Th17/Treg responses, and IL-23 expression in lung dendritic cells (DCs) were assessed, and the contribution of Th17 cells was examined by adoptive transfer. In parallel, DCs were cocultured with naïve CD4T cells in the presence of Hyper-IL-6 (an IL-6/sIL-6R fusion protein that activates IL-6-signaling) with or without sgp130 to quantify DC-derived IL-23 and Th17 differentiation; additionally, DCs conditioned with Hyper-IL-6 with or without sgp130 were delivered intratracheally to establish a DC-transfer asthma model. In neutrophilic asthma, bronchoalveolar lavage fluid (BALF) levels of IL-6/sIL-6R complex were elevated and positively associated with neutrophil counts and IL-17 production. Blockade of IL-6-signaling with sgp130 attenuated airway neutrophilia, reduced Th17 polarization, increased Treg response, and decreased IL-23 expression in lung DCs, whereas adoptive transfer of Th17 cells partially abrogated these protective effects. Consistently, Hyper-IL-6 increased IL-23 expression in DCs and promoted Th17 differentiation, both of which were suppressed by sgp130. Moreover, airway transfer of Hyper-IL-6-conditioned DCs induced neutrophilic airway inflammation and Th17 polarization, while transfer of DCs conditioned with Hyper-IL-6 plus sgp130 markedly mitigated these responses. Collectively, IL-6 trans-signaling promotes Th17 polarization in neutrophilic asthma by enhancing DC IL-23 production, thereby driving neutrophilic airway inflammation, and selective inhibition with sgp130 may represent a mechanistically targeted therapeutic strategy.