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

Abstract

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 (TH17) 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+ TH17 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 p16INK4a 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 TH17 immune response and the senescence response to implanted synthetic materials introduces new targets for therapeutic intervention in the foreign body response.

Senolytics for Cancer Therapy: Is All that Glitters Really Gold?

“…Notably, the senolytic action of ABT-263 appears to depend on inhibition of BCL-X L and/or BCL-W, while BCL-2 inhibition is dispensable [84,86]. Similar to D+Q, ABT-263 was successful in eliminating senescent cell populations in several disease models including aging-associated bone loss [87], radiation-induced lung fibrosis [88], lung emphysema [89], uterine leiomyoma [90], tau-dependent neurodegenerative disease [91], radiation-induced neurodegeneration [92], myocardial infarction (including ischemia-reperfusion injury) [93,94], heart failure [95], pulmonary hypertension [96], insulin resistance [97], osteoarthritis [98,99], synthetic implant-mediated fibrosis [100], and Duchenne muscular dystrophy [101]. ABT-263 is currently a cornerstone in preclinical studies of senolysis and remains a promising drug for use against both liquid and solid tumors [102][103][104].…”

Dissecting the microenvironment around biosynthetic scaffolds in murine skin wound healing

“…IL-17 secreted by group 3 innate lymphoid cells, γδ T cells and CD4+ adaptive T cells (Th17) can modulate extracellular matrix organization and fibrosis. (16,17) Previous studies usually focused on certain types of immune cells, like macrophages, and explored their roles in the host response. However, the immune response is concomitantly regulated by various immune cells, whose phenotype and function are dictated by external and internal signals.…”

“…By contrast, in type 2 immune response, T helper 2 (Th2) cells produce cytokines like IL-4 and IL-13, which regulate the polarization of macrophages towards an anti-inflammatory M2 activation (9, 10). More recently, a type 17 immune response was reported to promote chronic fibrosis in tissue around implants (11, 12). In summary, previous studies usually focused on certain types of immune cells, like macrophages, and explored their roles in the host response.…”

An immunologically active, adipose-derived extracellular matrix biomaterial for soft tissue reconstruction: concept to clinical trial

“…Previous preclinical studies showed that a proregenerative macrophage phenotype is required for repair using biological ECM scaffolds, and that a local TH2 response is required for promoting the pro-regenerative macrophage phenotype that develops in response to biological scaffolds 11 . This type 2 mediated response contrasts the macrophage and T cell phenotypes that develop around synthetic implants which includes inflammatory macrophages fusing to form foreign body giant cells and the more recently defined TH17 T cell and senescent cell phenotypes 28 . The proregenerative or "M2" macrophage response to biological scaffolds was validated clinically in biopsies from large muscle defects treated with small intestinal submucosa-derived ECM 29…”