The Immunological Function of CXCR2 in the Liver During Sepsis

Overview

Journal J Inflamm (Lond)

Publisher Biomed Central

Date 2022 Dec 1

PMID 36451225

Authors

Na Liu

Michael Bauer

Adrian T Press

Affiliations

Soon will be listed here.

Abstract

Background: The chemokine receptor CXCR2 and its ligands, especially CXCL8, are crucial mediators for the progression of liver inflammation and liver failure in sepsis. Neutrophils have the highest CXCR2 expression in mice and humans, and their activation via CXCL8 facilitates their migration to the inflamed liver for the clearance of the pathogens and, in turn, the inflammation.

Main Body: In sepsis, the inflammatory insult causes extensive neutrophil migration to the liver that overwhelms the immune response. To compensate for the strong receptor activation, CXCR2 desensitizes, incapacitating the immune cells to efficiently clear pathogens, causing further life-threatening liver damage and uncontrolled pathogen spread.

Conclusion: CXCR2 function during infection strongly depends on the expressing cell type. It signals pro- and anti-inflammatory effects that may prompt novel cell-type-specific CXCR2-directed therapeutics.

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References

Peng H, Tian Z . Re-examining the origin and function of liver-resident NK cells. Trends Immunol. 2015; 36(5):293-9. DOI: 10.1016/j.it.2015.03.006. View

Moss R, Mistry S, Konstan M, Pilewski J, Kerem E, Tal-Singer R . Safety and early treatment effects of the CXCR2 antagonist SB-656933 in patients with cystic fibrosis. J Cyst Fibros. 2012; 12(3):241-8. DOI: 10.1016/j.jcf.2012.08.016. View

Tang J, Yan Z, Feng Q, Yu L, Wang H . The Roles of Neutrophils in the Pathogenesis of Liver Diseases. Front Immunol. 2021; 12:625472. PMC: 7982672. DOI: 10.3389/fimmu.2021.625472. View

Khandaker M, Mitchell G, Xu L, Andrews J, Singh R, Leung H . Metalloproteinases are involved in lipopolysaccharide- and tumor necrosis factor-alpha-mediated regulation of CXCR1 and CXCR2 chemokine receptor expression. Blood. 1999; 93(7):2173-85. View

Poisson J, Lemoinne S, Boulanger C, Durand F, Moreau R, Valla D . Liver sinusoidal endothelial cells: Physiology and role in liver diseases. J Hepatol. 2016; 66(1):212-227. DOI: 10.1016/j.jhep.2016.07.009. View

Ye D, Yang K, Zang S, Lin Z, Chau H, Wang Y . Lipocalin-2 mediates non-alcoholic steatohepatitis by promoting neutrophil-macrophage crosstalk via the induction of CXCR2. J Hepatol. 2016; 65(5):988-997. DOI: 10.1016/j.jhep.2016.05.041. View

Smith M, Olson T, Ley K . CXCR2- and E-selectin-induced neutrophil arrest during inflammation in vivo. J Exp Med. 2004; 200(7):935-9. PMC: 2213284. DOI: 10.1084/jem.20040424. View

Ren X, Carpenter A, Hogaboam C, Colletti L . Mitogenic properties of endogenous and pharmacological doses of macrophage inflammatory protein-2 after 70% hepatectomy in the mouse. Am J Pathol. 2003; 163(2):563-70. PMC: 1868215. DOI: 10.1016/S0002-9440(10)63684-X. View

Wu W, Sun S, Wang Y, Zhao R, Ren H, Li Z . Circulating Neutrophil Dysfunction in HBV-Related Acute-on-Chronic Liver Failure. Front Immunol. 2021; 12:620365. PMC: 7947208. DOI: 10.3389/fimmu.2021.620365. View

10.

Haridoss S, Yovchev M, Schweizer H, Megherhi S, Beecher M, Locker J . Activin A is a prominent autocrine regulator of hepatocyte growth arrest. Hepatol Commun. 2018; 1(9):852-870. PMC: 5721463. DOI: 10.1002/hep4.1106. View

11.

Darden D, Bacher R, Brusko M, Knight P, Hawkins R, Cox M . Single-Cell RNA-seq of Human Myeloid-Derived Suppressor Cells in Late Sepsis Reveals Multiple Subsets With Unique Transcriptional Responses: A Pilot Study. Shock. 2020; 55(5):587-595. PMC: 8019679. DOI: 10.1097/SHK.0000000000001671. View

12.

Darcy C, Minigo G, Piera K, Davis J, McNeil Y, Chen Y . Neutrophils with myeloid derived suppressor function deplete arginine and constrain T cell function in septic shock patients. Crit Care. 2014; 18(4):R163. PMC: 4261583. DOI: 10.1186/cc14003. View

13.

Rios-Santos F, Alves-Filho J, Souto F, Spiller F, Freitas A, Lotufo C . Down-regulation of CXCR2 on neutrophils in severe sepsis is mediated by inducible nitric oxide synthase-derived nitric oxide. Am J Respir Crit Care Med. 2006; 175(5):490-7. DOI: 10.1164/rccm.200601-103OC. View

14.

Wu Y, Stabach P, Michaud M, Madri J . Neutrophils lacking platelet-endothelial cell adhesion molecule-1 exhibit loss of directionality and motility in CXCR2-mediated chemotaxis. J Immunol. 2005; 175(6):3484-91. DOI: 10.4049/jimmunol.175.6.3484. View

15.

Trefts E, Gannon M, Wasserman D . The liver. Curr Biol. 2017; 27(21):R1147-R1151. PMC: 5897118. DOI: 10.1016/j.cub.2017.09.019. View

16.

Luther S, Cyster J . Chemokines as regulators of T cell differentiation. Nat Immunol. 2001; 2(2):102-7. DOI: 10.1038/84205. View

17.

Le T, Reeves R, McKinnon L . The functional diversity of tissue-resident natural killer cells against infection. Immunology. 2022; 167(1):28-39. DOI: 10.1111/imm.13523. View

18.

Leslie J, Mackey J, Jamieson T, Ramon-Gil E, Drake T, Fercoq F . CXCR2 inhibition enables NASH-HCC immunotherapy. Gut. 2022; . PMC: 9484388. DOI: 10.1136/gutjnl-2021-326259. View

19.

Ishida Y, Kondo T, Kimura A, Tsuneyama K, Takayasu T, Mukaida N . Opposite roles of neutrophils and macrophages in the pathogenesis of acetaminophen-induced acute liver injury. Eur J Immunol. 2006; 36(4):1028-38. DOI: 10.1002/eji.200535261. View

20.

Schraufstatter I, Chung J, Burger M . IL-8 activates endothelial cell CXCR1 and CXCR2 through Rho and Rac signaling pathways. Am J Physiol Lung Cell Mol Physiol. 2001; 280(6):L1094-103. DOI: 10.1152/ajplung.2001.280.6.L1094. View