Graft IL-33 regulates infiltrating macrophages to protect against chronic rejection.

Autor: Li T; Department of Surgery and.; Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; Department of Kidney Transplantation and., Zhang Z; Department of Surgery and.; Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; Department of Organ Transplantation and General Surgery, Second Xiangya Hospital of Central South University, Changsha, China., Bartolacci JG; Department of Surgery and.; McGowan Institute for Regenerative Medicine and., Dwyer GK; Department of Surgery and.; Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Liu Q; Department of Surgery and.; Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; Southern University of Science and Technology, Shenzhen, China., Mathews LR; Department of Surgery and.; Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Velayutham M; Department of Surgery and.; Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; Pittsburgh Heart, Lung, and Blood, Vascular Medicine Institute and.; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Roessing AS; Department of Surgery and.; Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Lee YC; McGowan Institute for Regenerative Medicine and.; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Dai H; Department of Surgery and.; Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; Department of Kidney Transplantation and., Shiva S; Pittsburgh Heart, Lung, and Blood, Vascular Medicine Institute and.; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Oberbarnscheidt MH; Department of Surgery and.; Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Dziki JL; Department of Surgery and.; McGowan Institute for Regenerative Medicine and., Mullet SJ; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Health Sciences Metabolomics and Lipidomics Core and.; Clinical Translational Science Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Wendell SG; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.; Health Sciences Metabolomics and Lipidomics Core and.; Clinical Translational Science Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Wilkinson JD; Department of Pediatrics, Vanderbilt School of Medicine, Nashville, Tennessee, USA., Webber SA; Department of Pediatrics, Vanderbilt School of Medicine, Nashville, Tennessee, USA., Wood-Trageser M; Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; Department of Pathology and., Watkins SC; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Demetris AJ; Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; McGowan Institute for Regenerative Medicine and.; Department of Pathology and., Hussey GS; Department of Surgery and.; McGowan Institute for Regenerative Medicine and., Badylak SF; Department of Surgery and.; McGowan Institute for Regenerative Medicine and.; Department of Bioengineering, University of Pittsburgh, Pittsburgh, Pennsylvania, USA., Turnquist HR; Department of Surgery and.; Thomas E. Starzl Transplantation Institute, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; McGowan Institute for Regenerative Medicine and.; Department of Immunology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Jazyk: angličtina
Zdroj: The Journal of clinical investigation [J Clin Invest] 2020 Oct 01; Vol. 130 (10), pp. 5397-5412.
DOI: 10.1172/JCI133008
Abstrakt: Alarmins, sequestered self-molecules containing damage-associated molecular patterns, are released during tissue injury to drive innate immune cell proinflammatory responses. Whether endogenous negative regulators controlling early immune responses are also released at the site of injury is poorly understood. Herein, we establish that the stromal cell-derived alarmin interleukin 33 (IL-33) is a local factor that directly restricts the proinflammatory capacity of graft-infiltrating macrophages early after transplantation. By assessing heart transplant recipient samples and using a mouse heart transplant model, we establish that IL-33 is upregulated in allografts to limit chronic rejection. Mouse cardiac transplants lacking IL-33 displayed dramatically accelerated vascular occlusion and subsequent fibrosis, which was not due to altered systemic immune responses. Instead, a lack of graft IL-33 caused local augmentation of proinflammatory iNOS+ macrophages that accelerated graft loss. IL-33 facilitated a metabolic program in macrophages associated with reparative and regulatory functions, and local delivery of IL-33 prevented the chronic rejection of IL-33-deficient cardiac transplants. Therefore, IL-33 represents what we believe is a novel regulatory alarmin in transplantation that limits chronic rejection by restraining the local activation of proinflammatory macrophages. The local delivery of IL-33 in extracellular matrix-based materials may be a promising biologic for chronic rejection prophylaxis.
Databáze: MEDLINE
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