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

Zou, Huijuan; Yang, Yan; Gao, Ming; Zhang, B.; Ming, Bingxia; Sun, Yan; Chen, H.; Tang, Xuhuan; Chen, Z.; Xiong, Ping; Xu, Yong; Fang, Min; Tan, Zheng; Gong, Feili; Zheng, Fang

doi:10.1111/ajt.12781

Cited by 45 publications

(44 citation statements)

References 61 publications

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“…7 This can lead to the production of proinflammatory cytokines (ie, IL-1α and IL-1β) and other mediators that further propagate tissue damage 8 and cell death by initiating an autoamplification loop. [12][13][14] Kidney injury molecule-1 (KIM-1, also known as TIM-1 15 ) is a type 1 transmembrane glycoprotein that is upregulated on renal PTECs following injury. 11 HMGB1 is released into circulation from many types of allografts after transplantation and inhibiting its function has been shown to dampen alloresponses and even prolong graft survival in several preclinical models.…”

Section: Introductionmentioning

confidence: 99%

Donor kidney injury molecule-1 promotes graft recovery by regulating systemic necroinflammation

Lee

Ismail

Zhang

et al. 2018

American Journal of Transplantation

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Ischemia-reperfusion injury during kidney transplantation predisposes to delayed graft function, rejection, and premature graft failure. Exacerbation of tissue damage and alloimmune responses may be explained by necroinflammation: an autoamplification loop of cell death and inflammation, which is mediated by the release of damage-associated molecular patterns (eg, high-mobility group box-1; HMGB1) from necrotic cells that activate both innate and adaptive immune pathways. Kidney injury molecule-1 (KIM-1) is a phosphatidylserine receptor that is upregulated on injured proximal tubular epithelial cells and enables them to clear apoptotic and necrotic cells. Here we show a pivotal role for clearance of dying cells in regulating necroinflammation in a syngeneic murine kidney transplant model. We found persistent KIM-1 expression in KIM-1 kidney grafts posttransplantation. Compared to recipients of KIM-1 kidneys, recipients of KIM-1 kidneys exhibited significantly more renal dysfunction, apoptosis and necrosis, tubular obstruction, and graft failure. KIM-1 grafts also had more inflammatory cytokines, infiltrating neutrophils, and macrophages compared to KIM-1 grafts. Most significantly, passive release of HMGB1 from apoptotic and necrotic cells led to dramatically higher serum HMGB1 levels and increased proinflammatory macrophages in recipients of KIM-1 grafts. Our data identify an endogenous protective mechanism against necroinflammation in kidney grafts that may be of therapeutic relevance in transplantation.

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Section: Introductionmentioning

confidence: 99%

Donor kidney injury molecule-1 promotes graft recovery by regulating systemic necroinflammation

Lee

Ismail

Zhang

et al. 2018

American Journal of Transplantation

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“…Still, pro-inflammatory cytokines like IFN-γ [77], IL-2 [78], IL-4 [79], are also necessary for tolerance induction [76]. Likewise, the most studied alarmin, high mobility group box 1, also exhibits both pro-inflammatory [35, 80] and tolerogenic properties [81]. These publications and recent studies of IL-33, suggest we may need to alter our thinking about self-derived immunomodulatory stimuli in alloimmunity and protocol for tolerance induction.…”

Section: Resultsmentioning

confidence: 99%

Controlling the burn and fueling the fire

Liu

Turnquist

2016

Current Opinion in Organ Transplantation

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Purpose of review To provide a general update on recent developments in the immunobiology of IL-33 and IL-33-targeted immune cells. We also discuss emerging concepts regarding the potential role IL-33 appears to play in altering alloimmune responses mediating host-versus-graft and graft-versus-host alloresponses. Recent findings Stromal cells and leukocytes display regulated expression of IL-33 and may actively or passively secrete this pleotropic cytokine. ILC2 and a large proportion of tissue resident Treg express membrane-bound ST2, the IL-33 receptor. While Treg are appreciated suppressors of the inflammatory function of immune cells, both ILC2s and tissue resident Treg could play key roles in tissue repair and homeostasis. The functions of IL-33 in transplantation are poorly understood. However, like other disease models, the functions of IL-33 in alloimmunity appear to be quite pleiotropic. IL-33 is associated with immune regulation and graft protection in cardiac transplant settings. Yet, it is highly pro-inflammatory and stimulates lethal graft-versus-host disease (GVHD) through its capacity to stimulate Type 1 immunity. Summary Intensive studies on IL-33/ST2 signaling pathways and ST2+ cell populations in solid organ and cell transplantation are warranted. A better understanding of this important pathway will provide promising therapeutic targets controlling pathogenic alloimmune responses, as well as potentially facilitating the function of regulatory and reparative immune cells post-transplantation.

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“…In addition to complement-mediated IRI, recent work has demonstrated the upregulation of HMGB1 protein may further enhance endothelial activation by activation of Toll-like receptor (TLR) 4 and MyD88 signaling (62). Blockade of HMGB1 and each of these downstream effectors correlated with reduced ischemic damage, implicating its role as an enhancer of ischemia-induced vascular inflammation (63).…”

Section: Other Contributors To the Development Of Avmentioning

confidence: 99%

Recent advances in allograft vasculopathy

Merola

Jane‐wit²,

Pober³

2017

Current Opinion in Organ Transplantation

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Purpose of review Despite considerable advances in controlling acute rejection, the longevity of cardiac and renal allografts remains significantly limited by chronic rejection in the form of allograft vasculopathy (AV). This review discusses recently reported mechanistic insights of AV pathogenesis as well recent clinical evaluations of new therapeutic approaches. Recent findings Although adaptive immunity is the major driver of AV, natural killer cells mediate vasculopathic changes in a transplanted mouse heart following treatment with donor-specific antibody (DSA). However, NK cells may also dampen chronic inflammatory responses by killing donor-derived tissue-resident CD4 T cells that provide help to host B cells, the source of DSA. DSA may directly contribute to vascular inflammation by inducing intracellular signaling cascades that upregulate leukocyte adhesion molecules, facilitating recruitment of neutrophils and monocytes. DSA-mediated complement activation additionally enhances endothelial alloimmunogenicity through activation of non-canonical NF-κB signaling. New clinical studies evaluating mTOR and proteasome inhibitors to target these pathways have been reported. Summary AV is a pathology resultant from several innate and adaptive alloimmune responses. Mechanistic insights from preclinical studies have identified agents that are currently being investigated in clinical trials.

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

Cited by 45 publications

References 61 publications

Donor kidney injury molecule-1 promotes graft recovery by regulating systemic necroinflammation

Donor kidney injury molecule-1 promotes graft recovery by regulating systemic necroinflammation

Controlling the burn and fueling the fire

Recent advances in allograft vasculopathy

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