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Sterile inflammation in thoracic transplantation

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Abstract

The life-saving benefits of organ transplantation can be thwarted by allograft dysfunction due to both infectious and sterile inflammation post-surgery. Sterile inflammation can occur after necrotic cell death due to the release of endogenous ligands [such as damage-associated molecular patterns (DAMPs) and alarmins], which perpetuate inflammation and ongoing cellular injury via various signaling cascades. Ischemia–reperfusion injury (IRI) is a significant contributor to sterile inflammation after organ transplantation and is associated with detrimental short- and long-term outcomes. While the vicious cycle of sterile inflammation and cellular injury is remarkably consistent amongst different organs and even species, we have begun understanding its mechanistic basis only over the last few decades. This understanding has resulted in the developments of novel, yet non-specific therapies for mitigating IRI-induced graft damage, albeit with moderate results. Thus, further understanding of the mechanisms underlying sterile inflammation after transplantation is critical for identifying personalized therapies to prevent or interrupt this vicious cycle and mitigating allograft dysfunction. In this review, we identify common and distinct pathways of post-transplant sterile inflammation across both heart and lung transplantation that can potentially be targeted.

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Abbreviations

ACR:

Acute cellular rejection

ALLN:

N-acetyl-leu-leu-norleucinal

AM:

Alveolar macrophage

AP-1:

Activator protein 1

APC:

Antigen-presenting cell

ASC:

Apoptosis-associated speck-like protein containing a CARD

ATP:

Adenosine triphosphate

BALF:

Bronchoalveolar lavage fluid

BOS:

Bronchiolitis obliterans syndrome

Ca2 + :

Ionized calcium

CAM:

Cellular adhesion molecule

CARD:

Caspase activation and recruitment domain

C3:

Complement factor 3

CCL2:

Chemokine ligand 2

CCR2:

CC chemokine receptor 2

CLAD:

Chronic lung allograft dysfunction

CM:

Classical monocyte

CTLA4:

Cytotoxic T-lymphocyte-associated protein 4

CXCL1:

Chemokine (C-X-C motif) ligand 1

CXCL2:

Chemokine (C-X-C motif) ligand 2

CXCL10:

Chemokine (C-X-C motif) ligand 10

DAMP:

Damage-associated molecular pattern

DC:

Dendritic cell

eATP:

Extracellular adenosine triphosphate

ERK:

Extracellular signal-regulated kinase

Fer-1:

Ferrostatin-1

FoxP3:

Forkhead box P3

FPR1:

Formylated peptide receptor 1

HA:

Hyaluronic acid or hyaluronan

HMGB1:

High-mobility group box 1

HMW-HA:

High molecular weight hyaluronic acid

HSP:

Heat shock protein

ICAM-1:

Intercellular adhesion molecule 1

IFN:

Interferon

IgG:

Immunoglobulin G

IL-1α:

Interleukin-1 alpha

IL-1β:

Interleukin-1 beta

IL-1R:

Interleukin-1 receptor

IL-6:

Interleukin-6

IL-8:

Interleukin-8

IL-12:

Interleukin-12

IL-17:

Interleukin-17

IL-18:

Interleukin-18

IL-18BP:

Interleukin-18 binding protein

IL-23:

Interleukin-23

IL-33:

Interleukin-33

IKK:

IκB kinase

iNKT:

Invariant natural killer T cells

IRAK:

Interleukin-1 receptor-associated kinase

IRF3:

Interferon regulatory factor 3

IRI:

Ischemia–reperfusion injury

JNK:

C-Jun N-terminal kinase

KC:

Keratinocyte chemoattractant

KL6:

Krebs von den Lungen 6, a mucin-like glycoprotein

LDH:

Lactate dehydrogenase

HMW-H:

High molecular weight hyaluronic acid

LMW-HA:

Low molecular weight hyaluronic acid

MAPK:

Mitogen-activated protein kinase

MCP-1:

Monocyte chemoattractant protein 1

MIP-1:

Macrophage inflammatory protein 1

MIP-2:

Macrophage inflammatory protein 2

miR-26a:

MicroRNA 26a

MLKL:

Mixed lineage kinase-like pseudokinase

mo-DC:

Monocyte-derived dendritic cell

Mo-AMs:

Monocyte-derived alveolar macrophages

MPTP:

Mitochondrial permeability transition pore

mtDNA:

Mitochondrial DNA

MyD88:

Myeloid differentiation primary response 88

NCM:

Nonclassical monocytes

Nec-1:

Necrostatin-1

Nec-1 s:

Necrostatin-1 stable

NET:

Neutrophil extracellular trap

NF-κB:

Nuclear factor kappa-light-chain enhancer of B cells

NK:

Natural killer cell

NLRP3:

NOD-LRR-and pyrin domain-containing 3 protein

NO:

Nitric oxide

NOX2:

NADPH oxidase

NT-proBNP:

N-terminal prohormone of brain natriuretic peptide

NYHA:

New York Heart Association

oATP:

Oxidized ATP

PAMP:

Pathogen-associated molecular pattern

PBMC:

Peripheral blood mononuclear cells

PGD:

Primary graft dysfunction

PKCδ:

Protein kinase C-δ

PRR:

Pattern recognition receptor

RAGE:

Receptor for advanced glycation end products

RIPK:

Receptor-interacting protein kinase

ROS:

Reactive oxygen species

SGT1:

Suppressor of G2 allele of S-phase kinase-associated protein 1

sRAGE:

Soluble receptor for advanced glycation end products

ST2:

Suppressor of tumorigenicity 2

STAT3:

Signal transducer and activator of transcription 3

TIR:

Toll–interleukin 1 receptor

TIRAP:

Toll–interleukin 1 receptor adaptor protein

TLR:

Toll-like receptor

TNF-α:

Tumor necrosis factor alpha

TNFR1:

Tumor necrosis factor receptor 1

TnT:

Troponin T

TRIF:

TIR-domain-containing adaptor-inducing interferon-β

TRAM:

TRIF adaptor molecule

WT:

Wildtype

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Funding for this work was provided by the Children’s Discovery Institute of Washington University and St. Louis Children’s Hospital (H.S.K.), National Institutes of Health (K08-HL148510 to H.S.K., T32-HL007776 to C.C.F., and 5T32-HL007317-42 to A.I.B.), American Lung Association (Biomedical Research Grant to H.S.K.).

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Correspondence to C. Corbin Frye or Amit I. Bery.

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Frye, C.C., Bery, A.I., Kreisel, D. et al. Sterile inflammation in thoracic transplantation. Cell. Mol. Life Sci. 78, 581–601 (2021). https://doi.org/10.1007/s00018-020-03615-7

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  • DOI: https://doi.org/10.1007/s00018-020-03615-7

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