IL-17A produced by αβ T cells drives airway hyper-responsiveness in mice and enhances mouse and human airway smooth muscle contraction

Abstract

Emerging evidence suggests that the TH17 subset of αβ T cells contributes to the development of allergic asthma. In this study we found that mice lacking αvβ8 on dendritic cells failed to generate TH17 cells in the lung and were protected from AHR in response to house dust mite and ovalbumin sensitization and challenge. Because loss of TH17 cells inhibited airway narrowing without obvious effects on airway inflammation or epithelial morphology, we examined the direct effects of TH17 cytokines on mouse and human airway smooth muscle function. IL-17A enhanced contractile force generation through a NF-κB/RhoA/ROCK2 signaling cascade. Mice lacking integrin αvβ8 on dendritic cells showed impaired activation of this pathway after OVA sensitization and challenge, and the diminished contraction of tracheal rings from these mice was reversed by IL-17A. These data indicate that IL-17A produced by TH17 cells contributes to allergen-induced AHR through direct effects on airway smooth muscle.

Mfge8 suppresses airway hyperresponsiveness in asthma by regulating smooth muscle contraction

“…IL-13, TNF-α, and IL-17A each enhance calcium sensitivity through a signaling pathway consisting of NF-κB activation, increased RhoA and ROCK2 expression, and ROCK2 phosphorylation of MLCP (2)(3)(4)38). We show here that Mfge8 inhibits ASM contraction in part by suppressing this pathway.…”

“…Although a significant body of research has focused on understanding the effects of IL-13, IL-17A, and other cytokines on coordinating the immune response in asthma (17,23,(44)(45)(46), the importance of these mediators on ASM contractility has been more recently appreciated (2,4). Most of the therapeutic strategies in asthma target specific steps of the inflammatory response with varying success (47).…”

“…New insights into the pathogenesis of bronchoconstriction, especially as they relate to the ASM, are of significant clinical interest. The cytokines IL-13, IL-17A, and TNF-α, all of which are elevated in the airways of patients with asthma, regulate airway hyperresponsiveness (AHR) by increasing ASM calcium sensitivity (2)(3)(4)(5). The release of contractile agonists during airway inflammation causes excessive bronchoconstriction in sensitized ASM.…”

“…Cytokines enhance ASM calcium sensitivity and contraction through a signaling pathway involving NF-κB, ras homolog gene family, member A (RhoA), and ROCK2 (2)(3)(4). Activation of this pathway leads to phosphorylation and inactivation of MLC phosphatase (MLCP) by ROCK2 (4,7,8).…”

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

“…123 Recently, one study showed that IL-17 but not IL-17F directly drove pulmonary hyper-responsiveness by promoting smooth muscle contractions in the airway. 124 Because IL-17 also induces the production of mucins such as MUC5AC and MUC5B by airway epithelial cells, 125,126 these findings indicate that IL-17 may promote pulmonary allergies by inducing airway remodelling in addition to its inflammatory effects.…”