Alarmins, sequestered self-molecules containing damage-associated molecular patterns, are released during tissue injury to drive innate immune cell proinflammatory responses. Whether endogenous negative regulators controlling early immune responses are also released at the site of injury is poorly understood. Herein, we establish that the stromal cell–derived alarmin interleukin 33 (IL-33) is a local factor that directly restricts the proinflammatory capacity of graft-infiltrating macrophages early after transplantation. By assessing heart transplant recipient samples and using a mouse heart transplant model, we establish that IL-33 is upregulated in allografts to limit chronic rejection. Mouse cardiac transplants lacking IL-33 displayed dramatically accelerated vascular occlusion and subsequent fibrosis, which was not due to altered systemic immune responses. Instead, a lack of graft IL-33 caused local augmentation of proinflammatory iNOS⁺ macrophages that accelerated graft loss. IL-33 facilitated a metabolic program in macrophages associated with reparative and regulatory functions, and local delivery of IL-33 prevented the chronic rejection of IL-33–deficient cardiac transplants. Therefore, IL-33 represents what we believe is a novel regulatory alarmin in transplantation that limits chronic rejection by restraining the local activation of proinflammatory macrophages. The local delivery of IL-33 in extracellular matrix–based materials may be a promising biologic for chronic rejection prophylaxis.

Tissue engineering and regenerative medicine (TERM) may be defined as a translational discipline focused on the development of novel techniques, devices, and materials to replace or repair injured or diseased tissue and organs. The main approaches typically use cells, scaffolds, and signaling molecules, either alone or in combination, to promote repair and regeneration. Although cells are required to create new functional tissue, the source of cells, either from an exogenous allogeneic or autologous source or through the recruitment of endogenous (autologous) cells, is technically challenging and risks the host rejection of new tissue. Regardless of the cell source, these approaches also require appropriate instruction for proliferation, differentiation, and in vivo spatial organization to create new functional tissue. Such instruction is supplied through the microenvironment where cells reside, environments which largely consist of the extracellular matrix (ECM). The specific components of the ECM, and broadly the extracellular space, responsible for promoting tissue regeneration and repair, are not fully understood, however extracellular vesicles (EVs) found in body fluids and solid phases of ECM have emerged as key mediators of tissue regeneration and repair. Additionally, these EVs might serve as potential cell-free tools in TERM to promote tissue repair and regeneration with minimal risk for host rejection and adverse sequelae. The past two decades have shown a substantial interest in understanding the therapeutic role of EVs and their applications in the context of TERM. Therefore, the purpose of this review is to highlight the fundamental characteristics of EVs, the current pre-clinical and clinical applications of EVs in TERM, and the future of EV-based strategies in TERM.