High-mobility group box 1 accelerates early acute allograft rejection via enhancing IL-17⁺γδ T-cell response

Abstract

SummaryTh17 and cd T cells are the dominant IL-17-producing cell. We previously reported that high-mobility group box 1 (HMGB1) is critical in inducing IL-17-producing alloreactive T cells during early stage of acute allograft rejection. However, the role of cd T cells during this process and its implication in HMGB1-mediated allograft rejection are not fully understood. Here, we use a murine model of cardiac allograft transplantation to further study the role of HMGB1 and IL-17-producing cd T cells in acute allograft rejection. It was found that the expression of HMGB1 was increased in allograft, while blockade of HMGB1 suppressed IL-17 + cd T-cell response and inhibited the gene transcription of IL-23 and IL-1b. Furthermore, in vitro HMGB1 indirectly promoted the development of IL-17 + cd T cells by stimulating dendritic cells to produce IL-23 and IL-1b, meanwhile depletion of cd T cells in vivo prolonged allograft survival and reduced the level of IL-17 in serum. In conclusion, our findings inferred that increased HMGB1 expression could enhance IL-17 + cd T-cell response by promoting the secretion of IL-23 and IL-1b, while IL-17 + cd T cells contribute to the early stage of acute allograft rejection.

HMGB1 Is Involved in Chronic Rejection of Cardiac Allograft via Promoting Inflammatory-Like mDCs

“…Our previous studies have also demonstrated that HMGB1 plays critical roles in the pathogenesis of acute allograft rejection (16,17,19). This recent discovery of the extracellular role of HMGB1 as a proinflammatory cytokine has opened up a new field of research to study the role of HMGB1 in chronic allograft rejection.…”

“…Monoclonal anti-HMGB1 neutralizing antibody (isotype IgG) derived from NZB/W mouse (HMGB1 Ab) (19,23,24) was gifted by the Institute of Biophysics, Chinese Academy of Science (Beijing, China). Of HMGB1 Ab, 200 mg were injected into recipient intraperitoneally (i.p.…”

“…), from the day before transplantation, then twice a week till Week 4 after transplantation. The same amount of mouse IgG (Sigma-Aldrich, St. Louis, MO) served as controls (19).…”

“…Moser et al and our previous studies have demonstrated that blockade of extracellular HMGB1 or its receptor, the receptor for advanced glycation endproducts (RAGE), significantly delayed cardiac allograft acute rejection (16)(17)(18)(19), and HMGB1 played a pivotal role in the induction of IL-17-producing alloreactive T cells by stimulating DCs secretion of IL-6 (17). However, the roles of HMGB1 in the development of chronic rejection of cardiac allograft, especially CAV, are still unclear.…”

HMGB1 expression patterns during the progression of experimental autoimmune encephalomyelitis

“…In this study, we detected the nuclear expression of HMGB1 in some of astrocytes, microglia and a few neurons in adult mouse spinal cord, which supplies more information to characterize the expression of HMGB1 in CNS and helps in discovering the potential CNS specific functions of HMGB1. Extracellular HMGB1, which is released passively by death cells or actively by stimulated cells such as macrophages, has been reported to play a key role in autoimmune diseases (Magna and Pisetsky, 2014), allograft rejection (Xia et al, 2014), ischemic stroke (Hayakawa et al, 2012), traumatic brain injury (Laird et al, 2014), and neurodegenerative diseases (Fang et al, 2012) as an inflammatory mediator. MS/EAE is a CNS specific autoimmune disease, which happens in adult human being or is induced in adult animal.…”