Interleukin 17 and senescent cells regulate the foreign body response to synthetic material implants in mice and humans.

Elucidating the foreign body response: Synthetic materials are the building blocks for medical devices and implants but can induce a foreign body response after implantation, resulting in fibrous scar tissue encompassing the implant. Here, Chung et al. define the role of interleukin 17 (IL17) and cellular senescence in driving the foreign body response. The fibrous capsule from excised breast implants contained IL17-producing T cells and senescent stromal cells. These findings were further validated in a murine model, and the authors found that blocking the IL17 pathway or eliminating senescent cells mitigated local fibrosis around the implant. This study presents new potential therapeutic targets to reduce fibrosis associated with the foreign body response. Medical devices and implants made of synthetic materials can induce an immune-mediated process when implanted in the body called the foreign body response, which results in formation of a fibrous capsule around the implant. To explore the immune and stromal connections underpinning the foreign body response, we analyzed fibrotic capsules surrounding surgically excised human breast implants from 12 individuals. We found increased numbers of interleukin 17 (IL17)–producing γδ⁺ T cells and CD4⁺ T helper 17 (T_H17) cells as well as senescent stromal cells in the fibrotic capsules. Further analysis in a murine model demonstrated an early innate IL17 response to implanted synthetic material (polycaprolactone) particles that was mediated by innate lymphoid cells and γδ⁺ T cells. This was followed by a chronic adaptive CD4⁺ T_H17 cell response that was antigen dependent. Synthetic materials with varying chemical and physical properties implanted either in injured muscle or subcutaneously induced similar IL17 responses in mice. Mice deficient in IL17 signaling established that IL17 was required for the fibrotic response to implanted synthetic materials and the development of p16^INK4a senescent cells. IL6 produced by senescent cells was sufficient for the induction of IL17 expression in T cells. Treatment with a senolytic agent (navitoclax) that killed senescent cells reduced IL17 expression and fibrosis in the mouse implant model. Discovery of a feed-forward loop between the T_H17 immune response and the senescence response to implanted synthetic materials introduces new targets for therapeutic intervention in the foreign body response. [ABSTRACT FROM AUTHOR]