IL-17RC signaling in mesoderm-derived stromal cells is dispensable for skin neutrophil recruitment in murine imiquimod-induced psoriasis

Summary: Abstract Body: The pathogenesis of psoriasis in humans and the imiquimod (IMQ)-induced mouse model is strongly driven by members of the IL-17 cytokine family which signal not only to keratinocytes but also to dermal stromal cells such as fibroblasts. Signaling occurs through dimeric IL17 receptor (IL-17R) complexes, of which IL-17RA is a common component. It has been described that IL-17RA deletion within either keratinocytes or fibroblasts dramatically reduces neutrophilic inflammation in murine IMQ-induced psoriasis. Dimeric IL-17RA/IL-17RC is thought to be the major receptor complex involved; however, IL-17RA can also dimerize with other IL17R family members. We therefore sought to determine the dependency of neutrophil recruitment on IL-17RA/IL-17RC signaling in dermal fibroblasts using Twist2-driven Cre expression to delete Il17rc in mesoderm-derived tissues. Twist2-cre+ and Twist2-cre- littermates, as well as global IL17rc-/- knockout mice were subjected to 5 days of treatment with 5% imiquimod cream, then euthanized for analysis of neutrophilic skin inflammation by flow cytometry. While global IL17rc-/- knockout mice exhibited 10-fold (p<0.0001) fewer skin neutrophils relative to Twist2-cre- mice, Twist2-cre+ mice displayed equivalent neutrophilic infiltration to Twist2-cre- littermates. These data raise the possibility that alternative IL-17R complexes can fully compensate for the loss of IL-17RA/IL-17RC signaling in dermal fibroblasts to drive neutrophilic inflammation in the IMQ psoriasis model. Future experiments will use in vitro and ex vivo models of dermal fibroblasts with receptor antibody blockade to isolate the specific IL-17R signaling complexes responsible for neutrophil recruitment to the skin. Robert D. Clark¹, Kimberly Hinh¹, T. Parks Remcho¹, Jay K. Kolls¹ 1. Medicine, Tulane University School of Medicine, New Orleans, LA, United States. Cell Communication Networks and Stromal Biology