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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 ??+ 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 ??+ 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.

SUBMITTER: Chung L

PROVIDER: S-EPMC7219543 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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

Chung Liam L Maestas David R DR Lebid Andriana A Mageau Ashlie A Rosson Gedge D GD Wu Xinqun X Wolf Matthew T MT Tam Ada J AJ Vanderzee Isabel I Wang Xiaokun X Andorko James I JI Zhang Hong H Narain Radhika R Sadtler Kaitlyn K Fan Hongni H Čiháková Daniela D Le Saux Claude Jourdan CJ Housseau Franck F Pardoll Drew M DM Elisseeff Jennifer H JH

Science translational medicine 20200401 539

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<sup>+</sup> T cells a ...[more]

PMID: 32295900

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Project description:The foreign body response (FBR) to nitric oxide (NO)-releasing subcutaneous implants was compared between healthy and streptozotocin-induced diabetic swine by evaluating inflammation, collagen capsule formation, and angiogenesis. Steel wire substrates were first modified with polyurethane membranes capable of diverse NO-release kinetics (NO fluxes and release durations of 0.8-630.0 pmol cm-2 s-1 and 2-13 d, respectively). The NO-releasing materials were implanted in the subcutis for 3, 10, or 25 d for histological and immunohistochemical evaluation of the FBR. A delayed, more severe inflammatory response to control (i.e., non-NO-releasing) implants was observed in diabetic pigs relative to healthy swine. Regardless of the animal disease state, each NO-releasing implant tested elicited reduced inflammation compared to controls at both 3 and 10 d. However, only the NO-release materials capable of releasing low NO fluxes (0.8-3.3 pmol cm-2 s-1) for 7-13 d durations mitigated the inflammatory response at 25 d. Using immunohistochemical staining for the endothelial cell surface marker CD-31, we also observed poor blood vessel development at non-NO-releasing implants in diabetic swine. Relative to controls, NO-releasing implants with the longest NO-release duration (13 d) increased blood vessel densities by 47.1 and 70.4% in the healthy and diabetic pigs, respectively. In the healthy model, tissues surrounding the long NO-release materials contained sparse amounts of collagen, whereas implants with shorter NO-release durations (2, 3, and 7 d) were characterized with a dense collagen encapsulation layer, similar to controls. Collagen deposition in diabetic swine was inhibited, and unaffected by NO. These results emphasize several key differences in the FBR in the setting of acute onset diabetes. The observation that NO release counteracts the more severe FBR in diabetic swine while simultaneously promoting tissue integration may help guide the design of medical implants (e.g., glucose sensors) with improved performance for diabetes management.

Project description:Biodegradable plates have been used extensively in fracture fixation since the 1960s. They rarely cause stress-protection atrophy or problems requiring secondary plate removal, common complications seen with metallic plates. However, aseptic foreign-body reactions have been reported, sometimes years after the original implantation. Both inadequate polymer degradation and debris accumulation have been implicated as causes. The current generation of commercial biodegradable plates is formulated to minimize this complication by altering the ratio of polylactic and polyglycolic acids. This in vivo study compares the degree of local foreign-body reaction of two commercially available resorbable plates in rabbits. Two types of biodegradable plates were examined: poly(D/L)lactide acid (PDLLA) and polylactide-co-glycolide acid (PLGA). Each plate was placed into a periosteal pericalvarial pocket created beneath the anterior or posterior scalp of a rabbit. Humane killing occurred at 3, 6, and 12 months postoperatively. Foreign-body reaction was evaluated histologically. The PDLLA plates demonstrated marked local foreign-body reactions within the implant capsule as early as 3 months after implantation, with presence of inflammatory cells and granulomatous giant cells in close association with the implant material. All local foreign-body reactions were subclinical with no corresponding tissue swelling requiring drainage. PLGA plates did not demonstrate any signs of inflammatory reactions. In addition, the PLGA plates did not appear to resorb or integrate at 12 months. Neither PDLLA nor PLGA plates demonstrated inflammation of the soft tissue or adjacent bone outside the implant capsule. In our study, the PDLLA plates demonstrated histological evidence of foreign-body reaction that is confined within the implant capsule, which was not seen with the PLGA plates. This finding may be attributable to the lack of significant resorption seen in the PLGA plates. Both PDLLA and PLGA plates were biocompatible with the rabbit tissue environment and should be considered for continued use in craniofacial, maxillofacial, and orthopedic reconstruction.

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

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

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