Reparative and Maladaptive Inflammation in Tendon Healing

Abstract

Tendon injuries are common and debilitating, with non-regenerative healing often resulting in chronic disease. While there has been considerable progress in identifying the cellular and molecular regulators of tendon healing, the role of inflammation in tendon healing is less well understood. While inflammation underlies chronic tendinopathy, it also aids debris clearance and signals tissue repair. Here, we highlight recent findings in this area, focusing on the cells and cytokines involved in reparative inflammation. We also discuss findings from other model systems when research in tendon is minimal, and explore recent studies in the treatment of human tendinopathy to glean further insights into the immunobiology of tendon healing.

Keywords: regeneration; reparative inflammation; tendinopathy; tendon; wound healing.

FIGURE 1

Initiation of a type 1 and type 2 immune response. Following injury, distinct signals establish a type 1 or type 2 immune response. Release of pathogen-associated or damage-associated molecular patterns (PAMP/DAMP), bind toll-like receptors (TLRs) and stimulate release of inflammatory cytokines. Secretion of IL-12, primes conversion of naive CD4 T cells and macrophages (Mϕ) to form Th1 and M1 phenotypes, that secrete IFNγ, to sustain a type 1 immune environment. Together, stimulated neutrophils and M1 macrophages perform pathogen killing and cellular debridement of dead or dying cells to facilitate deposition of new ECM and recruitment of cells. Polarized Th1 T cells also produce IL17, which stimulates Th17 T cells and fibroblast activation. Type 2 immunity is initiated by secretion of IL4 or release of the alarmin IL33 from damaged cells. In addition, secretion of IL4 from accessory cells including eosinophils, type 2 innate lymphoid cells (ILC2s), and Tregs can also induce a type 2 immune response. IL4 drives conversion of naive CD4 T cells and macrophages to a Th2 T cell or M2 macrophage phenotype, respectively. M2 macrophages act downstream to phagocytose tissue debris, deposit ECM, and secrete growth factors to stimulate stem and progenitor cells. In addition, stimulated Tregs produce IL10 which resolves type 1 inflammation.

FIGURE 2

The wound healing cascade. The inflammatory response to wounding is highly orchestrated to follow four main programs after injury including hemostasis, type 1 inflammation, type 2 inflammation, and resolution. Clot and platelet plug formation stop bleeding and establish a source of cytokines that attract primarily innate myeloid cells including neutrophils, eosinophils, and macrophages. The initial immune environment is established by a type 1 response that promotes M1 macrophage polarization, that together with neutrophils perform pathogen killing to re-establish barrier protection and tissue debridement to clear dead tissue for cell recruitment and ECM deposition. Following, Tregs promote immune tolerance and resolution by mediating a switch to a type 2 inflammatory response. M2 polarized macrophages and Tregs facilitate ECM deposition, and secretion of growth factors. Stem cell (SC) and progenitor cell (PC) stimulation via secreted growth factors results in proliferation and recruitment to the re-modeled wound niche, where they facilitate long term tissue remodeling and repair.

FIGURE 3

Counter-regulation and balance of type 1 and type 2 inflammatory responses dictate repair outcome. Stimulation of a type 1 immune response produces cytokines that stimulate innate (IL1β, TNFα, IL6, and IL1) and adaptive (IL12, IFNγ, and IL17) immune response. Similarly, release of IL4, IL5, and IL33 induces a type 2 immune response, while IL10 acts primarily to resolve acutely produced type 1 cytokines. Type 1 and type 2 cytokines counter-regulate, to establish the predominant immune signature. Importantly, effective tissue regeneration depends on the balance of inflammatory programs, where overactive type 1 inflammation can result in sudden inflammatory response syndrome (SIRS) or cytokine storm, while excessive type 2 inflammation drives tissue fibrosis.