Monocyte proinflammatory phenotypic control by ephrin type A receptor 4 mediates neural tissue damage.
| Title: | Monocyte proinflammatory phenotypic control by ephrin type A receptor 4 mediates neural tissue damage. |
|---|---|
| Authors: | Kowalski EA; Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, Virginia, USA.; Soliman E; Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, Virginia, USA.; Department of Pharmacology and Toxicology, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt.; Kelly C; Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, Virginia, USA.; School of Neuroscience, and.; Basso EKG; Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, Virginia, USA.; Leonard J; Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, Virginia, USA.; Pridham KJ; Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, Virginia, USA.; Ju J; Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, Virginia, USA.; Cash A; Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, Virginia, USA.; Hazy A; Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, Virginia, USA.; de Jager C; Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, Virginia, USA.; Kaloss AM; Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, Virginia, USA.; Ding H; Translational Biology Medicine and Health Graduate Program, Virginia Tech, Blacksburg, Virginia, USA.; Hernandez RD; Translational Biology Medicine and Health Graduate Program, Virginia Tech, Blacksburg, Virginia, USA.; Coleman G; School of Neuroscience, and.; Wang X; Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, Virginia, USA.; Olsen ML; School of Neuroscience, and.; Pickrell AM; School of Neuroscience, and.; Theus MH; Department of Biomedical Sciences and Pathobiology, Virginia Tech, Blacksburg, Virginia, USA.; School of Neuroscience, and.; Translational Biology Medicine and Health Graduate Program, Virginia Tech, Blacksburg, Virginia, USA.; Center for Engineered Health, Virginia Tech, Blacksburg, Virginia, USA. |
| Source: | JCI insight [JCI Insight] 2022 Aug 08; Vol. 7 (15). Date of Electronic Publication: 2022 Aug 08. |
| Publication Type: | Journal Article; Research Support, N.I.H., Extramural |
| Language: | English |
| Journal Info: | Publisher: American Society for Clinical Investigation Country of Publication: United States NLM ID: 101676073 Publication Model: Electronic Cited Medium: Internet ISSN: 2379-3708 (Electronic) Linking ISSN: 23793708 NLM ISO Abbreviation: JCI Insight Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Ann Arbor, Michigan : American Society for Clinical Investigation, [2016]- |
| MeSH Terms: | Brain Injuries*/metabolism ; Monocytes*/metabolism; Ephrins/metabolism ; Receptor, EphB2/metabolism ; Humans ; Phenotype ; Animals ; Mice |
| Abstract: | Circulating monocytes have emerged as key regulators of the neuroinflammatory milieu in a number of neuropathological disorders. Ephrin type A receptor 4 (Epha4) receptor tyrosine kinase, a prominent axon guidance molecule, has recently been implicated in the regulation of neuroinflammation. Using a mouse model of brain injury and a GFP BM chimeric approach, we found neuroprotection and a lack of significant motor deficits marked by reduced monocyte/macrophage cortical infiltration and an increased number of arginase-1+ cells in the absence of BM-derived Epha4. This was accompanied by a shift in monocyte gene profile from pro- to antiinflammatory that included increased Tek (Tie2 receptor) expression. Inhibition of Tie2 attenuated enhanced expression of M2-like genes in cultured Epha4-null monocytes/macrophages. In Epha4-BM-deficient mice, cortical-isolated GFP+ monocytes/macrophages displayed a phenotypic shift from a classical to an intermediate subtype, which displayed reduced Ly6chi concomitant with increased Ly6clo- and Tie2-expressing populations. Furthermore, clodronate liposome-mediated monocyte depletion mimicked these effects in WT mice but resulted in attenuation of phenotype in Epha4-BM-deficient mice. This demonstrates that monocyte polarization not overall recruitment dictates neural tissue damage. Thus, coordination of monocyte proinflammatory phenotypic state by Epha4 is a key regulatory step mediating brain injury. |
| References: | PLoS One. 2016 Jul 28;11(7):e0159930. (PMID: 27467069); J Trauma Acute Care Surg. 2015 Jan;78(1):184-91. (PMID: 25539220); Mediators Inflamm. 2016;2016:6373506. (PMID: 27199506); Crit Care. 2005 Sep 08;9(5):E21. (PMID: 16277705); Development. 2012 Nov;139(22):4105-9. (PMID: 23093422); Proc Natl Acad Sci U S A. 2014 Jul 8;111(27):9959-64. (PMID: 24958880); J Neuropathol Exp Neurol. 2012 Mar;71(3):242-50. (PMID: 22318127); J Immunol. 2017 Nov 15;199(10):3583-3591. (PMID: 28993515); Acta Neuropathol. 2002 Jun;103(6):541-9. (PMID: 12012085); J Clin Invest. 2012 Mar;122(3):787-95. (PMID: 22378047); Transl Psychiatry. 2020 Dec 8;10(1):423. (PMID: 33293506); Blood. 2010 Jan 21;115(3):e10-9. (PMID: 19965649); Neuron. 2017 Sep 13;95(6):1246-1265. (PMID: 28910616); J Immunol. 2011 Apr 1;186(7):4183-90. (PMID: 21368233); Oncotarget. 2018 Jul 03;9(51):29715-29726. (PMID: 30038715); J Neuroinflammation. 2019 Nov 11;16(1):210. (PMID: 31711546); EMBO Mol Med. 2013 Jun;5(6):843-57. (PMID: 23616286); Proc Natl Acad Sci U S A. 2017 Apr 25;114(17):4376-4381. (PMID: 28396439); Microcirculation. 2016 Feb;23(2):95-121. (PMID: 26614117); Nat Rev Immunol. 2011 Oct 10;11(11):762-74. (PMID: 21984070); J Neurosci Res. 2019 Jun;97(6):698-707. (PMID: 30746753); J Neurosci. 2018 Nov 7;38(45):9618-9634. (PMID: 30242049); Signal Transduct Target Ther. 2021 Aug 9;6(1):295. (PMID: 34366430); Front Physiol. 2018 May 01;9:419. (PMID: 29765329); Curr Opin Neurobiol. 2004 Jun;14(3):288-96. (PMID: 15194108); Science. 2016 Aug 19;353(6301):783-5. (PMID: 27540166); Immunity. 1998 Nov;9(5):677-86. (PMID: 9846489); J Neuroinflammation. 2010 Jan 18;7:5. (PMID: 20082712); Crit Rev Immunol. 2012;32(6):463-88. (PMID: 23428224); Blood. 2010 Oct 21;116(16):e74-80. (PMID: 20628149); J Mol Med (Berl). 2018 Sep;96(9):873-883. (PMID: 30030568); Curr Pharm Des. 2007;13(24):2507-18. (PMID: 17692019); Cell Chem Biol. 2017 Mar 16;24(3):293-305. (PMID: 28196613); PLoS One. 2018 Nov 1;13(11):e0202722. (PMID: 30383765); Trends Immunol. 2007 Dec;28(12):519-24. (PMID: 17981504); Neurosci Bull. 2011 Apr;27(2):115-22. (PMID: 21441973); J Clin Invest. 2020 Feb 3;130(2):1024-1035. (PMID: 31689239) |
| Grant Information: | R01 NS119540 United States NS NINDS NIH HHS; R01 NS121103 United States NS NINDS NIH HHS |
| Contributed Indexing: | Keywords: Neurological disorders; Neuroscience |
| Substance Nomenclature: | 0 (Ephrins); EC 2.7.10.1 (Receptor, EphB2) |
| Entry Date(s): | Date Created: 20220623 Date Completed: 20230919 Latest Revision: 20240518 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC9462496 |
| DOI: | 10.1172/jci.insight.156319 |
| PMID: | 35737458 |
| Database: | MEDLINE |
Journal Article; Research Support, N.I.H., Extramural