Fibroblast‐specific integrin‐alpha V differentially regulates type 17 and type 2 driven inflammation and fibrosis

Fibroproliferative diseases affect a significant proportion of the world's population. Despite this, core mechanisms driving organ fibrosis of diverse etiologies remain ill defined. Recent studies suggest that integrin‐alpha V serves as a master driver of fibrosis in multiple organs. Although diverse mechanisms contribute to the progression of fibrosis, TGF‐β and IL‐13 have emerged as central mediators of fibrosis during type 1/type 17, and type 2 polarized inflammatory responses, respectively. To investigate if integrin‐alpha V interactions or signaling is critical to the development of type 2 fibrosis, we analyzed fibroblast‐specific integrin‐alpha V knockout mice in three type 2‐driven inflammatory disease models. While we confirmed a role for integrin‐alpha V in type 17‐associated fibrosis, integrin‐alpha V was not critical to the development of type 2‐driven fibrosis. Additionally, our studies support a novel mechanism through which fibroblasts, via integrin‐alpha V expression, are capable of regulating immune polarization. We show that when integrin‐alpha V is deleted on fibroblasts, initiation of type 17 inflammation is inhibited leading to a deregulation of type 2 inflammation. This mechanism is most evident in a model of severe asthma, which is characterized by a mixed type 2/type 17 inflammatory response. Together, these findings suggest dual targeting of integrin‐alpha V and type 2 pathways may be needed to ameliorate fibrosis and prevent rebound of opposing pro‐fibrotic and inflammatory mechanisms. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.