Abstract
Interleukin-33 (IL-33) is a member of the IL-1 family of proteins that are produced by a variety of cell types in multiple tissues. Under conditions of cell injury or death, IL-33 is passively released from the nucleus and acts as an “alarmin” upon binding to its specific receptor ST2, which leads to proinflammatory or anti-inflammatory effects depending on the pathological environment. To date, numerous studies have investigated the roles of IL-33 in human and murine models of diseases of the nervous system, digestive system, pulmonary system, as well as other organs and systems, including solid organ transplantation. With graft rejection and ischemia-reperfusion injury being the most common causes of grafted organ failure or dysfunction, researchers have begun to investigate the role of IL-33 in the immune-related mechanisms of graft tolerance and rejection using heart transplantation models. In the present review, we summarize the identified roles of IL-33 as well as the corresponding mechanisms by which IL-33 acts within the progression of graft rejection after heart transplantation in animal models.
Highlights
In the field of heart transplantation in recent decades, much progress has been made in elucidating the mechanisms of cardiac graft rejection
Allograft rejection is considered one of the most common causes of graft failure after cardiac transplantation [1, 2]. Both acute and chronic rejection following heart transplantation are generally believed to result from a T helper 1 ( 1) cell-dominated immune response, which is characterized by the massive production of several certain types of proinflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-2 (IL-2), and interferon-c (IFN-c) [3,4,5]. ese cytokines have multiple effects on immune cells and the immune response, and their overproduction promotes graft destruction and dysfunction by mechanisms such as inducing the expression of costimulatory molecules, major histocompatibility complex- (MHC-) II, and chemokines in the graft; facilitating the induction of alloantigen-specific cytotoxicity; activating graft-infiltrating macrophages and macrophage-mediated effector mechanisms; and inducing alloantibody class switching to complement-fixing immunoglobulin G (IgG)2a [6,7,8,9,10,11,12]
Studies of Tregs in transplantation have focused on non-antigen-specific thymusderived naıve CD4+CD25+FOXP3+ T cells, which are fresh or activated by IL-2 only or IL-2 plus anti-CD3 antibody [23, 24]. ese cells express the transcription factor FOXP3, which inhibits IL-2 transcription, and promote the induction of transplant tolerance [25, 26], typically via cell contact-dependent and cell contact-independent mechanisms, ranging from cytokine release, receptor endocytosis, and purinergic signaling to cell cytotoxic mechanisms [27,28,29]
Summary
In the field of heart transplantation in recent decades, much progress has been made in elucidating the mechanisms of cardiac graft rejection. Us, they have a wide range of inhibitory effects on immune responses, including inhibition of the proliferation and activation of CD4+ and CD8+ T cells, suppression of B-cell responses, and regulation of macrophage and natural killer cell functions [30] In agreement with these observations, additional studies have reported that the balances of Tregs/ 17 and 1/ 2 are crucial for allograft survival [31,32,33]. Concordant xenotransplantation can almost overcome acute vascular rejection due to differences between species, and with the use of certain types of immunosuppressive agents or treatments, xenograft survival can be extended from several days to as long as 300 days [40, 42, 43, 45, 47] Despite these promising results, the underlying mechanisms of rejection remain to be demonstrated
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