Journal List > J Korean Soc Transplant > v.31(3) > 1034540

Lee: Immunologic Mechanism of Ischemia Reperfusion Injury in Transplantation

Abstract

Ischemia-reperfusion injury (IRI) is an inevitable consequence of organ transplantation that has major consequences for graft-and patient survival. During transplantation procedures, allografts are exposed to various periods of complete ischemia. Ischemic insult starts with brain death, and its associated hemodynamic disturbances continue during donor organ procurement, cold preservation, and implantation. Ischemia-reperfusion injury, which is a risk factor for acute graft injury, delayed graft function, and acute and chronic rejection, is triggered following reperfusion. Along the cascade of pathogenic events that accompany ischemic insults and cause IRI, there has been an appreciation for various immune mechanisms within the allograft itself. The pathophysiological events associated with IRI originate in signals derived from pattern recognition receptors (PRRs) expressed in the donor organ. Danger associated molecular patterns (DAMP) released from injured cells serve as ligands for PRRs expressed on many cells in the donor organ. Activation of PRR signaling in the donor organ leads to production of proinflammatory cytokines and activates the innate immune system, triggering adaptive immune responses as well as cell death signaling, ultimately worsening the initial ischemic injury. Accordingly, deciphering the inflammatory pathway of innate immunity in IRI may provide a good therapeutic target to block acute sterile inflammation caused by tissue damage.

Figures and Tables

Fig. 1

Schematic vies of innate inflammatory response. Abbreviations: DAMPs, Danger associated molecular patterns; TLRs, Toll-like receptors; TRAF6, TNF receptor-associated factor 6; MyD88, Myeloid differentiation primary response 88; TIRAP, Toll-interleukin 1 receptor (TIR) domain containing adaptor protein; TRAM, TRIF-related adaptor molecule; TRIF, TIR domain containing adaptor protein inducing interferon; IRAK1, Interleukin 1- receptor-associated kinase 1; TBK1, TANK binding kinase 1; IKK, Inhibitor of nuclear factor kappa-B kinase; NFkB, Nuclear factor kappa B; MAP3, MAP3 kinase; IFR3, Interferon regulatory factor 3.

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Fig. 2

ROS, cell stress/death, emission of DAMP axis initiating inflammation. Abbreviations: ROS, Reactive oxygen species; DAMP, Danger associated molecular pattern; PRR, pattern recognition receptor.

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Fig. 3

An example of model summarizing the role of the tubular epithelial cell/NK cell/neutrophil axis in kidney IRI. Injury to TECs following IRI (step 1) promotes release of HMGB1 (step 2). This molecule stimulates TECs to produce CCR5 chemokines through TLR2 activation (step 3) in an autocrine fashion. CCR5 chemokines in turn induce NK cell recruitment (step 5). Infiltrated NK cells use their cell surface molecule CD137 to stimulate CD137L on the surface of TECs (step 6). CD137L signaling results in the production of additional signaling molecules, CXCL1 and CXCL2, in TECs (step 7). Once infiltrated (step 8), neutrophils participate in active tissue destruction (step 9). Abbreviations: CCR5, chemokine receptors 5; CD137L, CD137 ligand; CXCL1, CXC chemokine ligand 1; CXCR2, C-X-C chemokine receptor type 2; HMGB1, High mobility group box-1 protein; IR, ischemia-reperfusion; NK cells, Natural killer cells; TECs, tubular epithelial cells; TLR2, toll like receptor 2. Reprinted from Fig. 6 of reference [80].

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Table 1

Type of pattern recognition receptor (PRR) and their ligand

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Abbreviations: iE-DAP, D-gamma-Glu-mDAP; LPS, Lipopolysaccharides; MDP, muramyl dipeptide; NOD, nucleotide-binding oligomerization domain; RLR, RIG-I-like receptors SAP, serum amyloid P.

Table 2

A list of prominent damage-associated molecular patterns (DAMPs) associated with cell stress/cell death and/or tissue injury

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Abbreviations: AIM2, absent in melanoma 2; CD, cluster of differentiation; cGAS, cyclic GMP-AMP synthase; cytDNA, cytosolic DNA; FEEL-1, fasciclin epidermal growth factor-like/common lymphatic endothelial and vascular endothelial receptor-1; mtDNA, mitochondrial DNA; NKG2D, natural-killer group 2, member D; NLRP3, NLR family, pyrin domain-containing protein 3; P2X7, purinergic P2X7 receptor; P2Y2, purinergic P2Y2 receptor; RAGE, receptor for advanced glycation end products; RIG-I, retinoic acid inducible gene I; SREC-1, scavenger receptor class f member 1; TIM, transmembrane immunoglobulin and mucin domain; TLR, toll-like receptor.

Notes

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government. (Ministry of Education) (NRF-2015R1D1A3A01020086).

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