Interleukin-17 and senescence regulate the foreign body response

Abstract

Abstract Synthetic biomaterials and medical devices suffer to varying levels from fibrosis via the foreign body response (FBR). To explore mechanistic connections between the immune response and fibrosis from the FBR, we first analyzed fibrotic capsule surrounding human breast implants and found increased numbers of interleukin (IL)17-producing γδ + T cells and CD4 + T H 17 cells as well as senescent cells. Further analysis in a murine model demonstrated an early innate IL17 response to synthetic implants, mediated by innate lymphoid cells and γδ + T cells, was followed by a chronic adaptive antigen dependent CD4 + T H 17 cell response. Mice deficient in IL17 signaling established that IL17 was required for the fibrotic response to materials and the development of p16 INK4a senescent cells. Treatment with a senolytic agent reduced IL17 expression and fibrosis. Discovery of a feed-forward loop between the T H 17 and senescence response to synthetic materials introduces new targets for therapeutic intervention in the foreign body response.