Monocyte proinflammatory phenotypic control by ephrin type A receptor 4 mediates neural tissue damage
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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Clinical investigation
2022-08-01
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| Series: | JCI Insight |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/jci.insight.156319 |
| _version_ | 1797634392263229440 |
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| author | Elizabeth A. Kowalski Eman Soliman Colin Kelly Erwin Kristobal Gudenschwager Basso John Leonard Kevin J. Pridham Jing Ju Alison Cash Amanda Hazy Caroline de Jager Alexandra M. Kaloss Hanzhang Ding Raymundo D. Hernandez Gabe Coleman Xia Wang Michelle L. Olsen Alicia M. Pickrell Michelle H. Theus |
| author_facet | Elizabeth A. Kowalski Eman Soliman Colin Kelly Erwin Kristobal Gudenschwager Basso John Leonard Kevin J. Pridham Jing Ju Alison Cash Amanda Hazy Caroline de Jager Alexandra M. Kaloss Hanzhang Ding Raymundo D. Hernandez Gabe Coleman Xia Wang Michelle L. Olsen Alicia M. Pickrell Michelle H. Theus |
| author_sort | Elizabeth A. Kowalski |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-11T12:08:12Z |
| format | Article |
| id | doaj.art-d48e080f6aa64183bed8ef43cb49ca19 |
| institution | Directory Open Access Journal |
| issn | 2379-3708 |
| language | English |
| last_indexed | 2024-03-11T12:08:12Z |
| publishDate | 2022-08-01 |
| publisher | American Society for Clinical investigation |
| record_format | Article |
| series | JCI Insight |
| spelling | doaj.art-d48e080f6aa64183bed8ef43cb49ca192023-11-07T16:24:24ZengAmerican Society for Clinical investigationJCI Insight2379-37082022-08-01715Monocyte proinflammatory phenotypic control by ephrin type A receptor 4 mediates neural tissue damageElizabeth A. KowalskiEman SolimanColin KellyErwin Kristobal Gudenschwager BassoJohn LeonardKevin J. PridhamJing JuAlison CashAmanda HazyCaroline de JagerAlexandra M. KalossHanzhang DingRaymundo D. HernandezGabe ColemanXia WangMichelle L. OlsenAlicia M. PickrellMichelle H. TheusCirculating 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.https://doi.org/10.1172/jci.insight.156319Neuroscience |
| spellingShingle | Elizabeth A. Kowalski Eman Soliman Colin Kelly Erwin Kristobal Gudenschwager Basso John Leonard Kevin J. Pridham Jing Ju Alison Cash Amanda Hazy Caroline de Jager Alexandra M. Kaloss Hanzhang Ding Raymundo D. Hernandez Gabe Coleman Xia Wang Michelle L. Olsen Alicia M. Pickrell Michelle H. Theus Monocyte proinflammatory phenotypic control by ephrin type A receptor 4 mediates neural tissue damage JCI Insight Neuroscience |
| title | Monocyte proinflammatory phenotypic control by ephrin type A receptor 4 mediates neural tissue damage |
| title_full | Monocyte proinflammatory phenotypic control by ephrin type A receptor 4 mediates neural tissue damage |
| title_fullStr | Monocyte proinflammatory phenotypic control by ephrin type A receptor 4 mediates neural tissue damage |
| title_full_unstemmed | Monocyte proinflammatory phenotypic control by ephrin type A receptor 4 mediates neural tissue damage |
| title_short | Monocyte proinflammatory phenotypic control by ephrin type A receptor 4 mediates neural tissue damage |
| title_sort | monocyte proinflammatory phenotypic control by ephrin type a receptor 4 mediates neural tissue damage |
| topic | Neuroscience |
| url | https://doi.org/10.1172/jci.insight.156319 |
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