Complement receptor C3aR1 controls neutrophil mobilization following spinal cord injury through physiological antagonism of CXCR2
| Autor: | Gail M. Williams, Frederic A. Meunier, Trisha Jogia, Jean-Pierre Levesque, Linda V. Blomster, Bianca Nowlan, Ellen R. Gillespie, Kate E. Campbell, Marc J. Ruitenberg, Xaria X. Li, Trent M. Woodruff, Esther Jacobson, Geoff W. Osborne, Faith H. Brennan, Kelli P. A. MacDonald, Stephen M. Taylor |
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| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 0301 basic medicine Neutrophils Inflammation Complement receptor Neuroprotection Receptors Interleukin-8B Mice Phosphatidylinositol 3-Kinases Young Adult 03 medical and health sciences Chemokine receptor 0302 clinical medicine Bone Marrow Cell Movement Cell Adhesion Animals Humans PTEN Tensin Medicine Receptor Anaphylatoxin C5a Spinal cord injury Spinal Cord Injuries PI3K/AKT/mTOR pathway Mice Knockout biology business.industry PTEN Phosphohydrolase General Medicine medicine.disease Receptors Complement Mice Inbred C57BL Disease Models Animal 030104 developmental biology Neutrophil Infiltration 030220 oncology & carcinogenesis Immunology biology.protein Wounds and Injuries Female medicine.symptom Transcriptome business Research Article |
| Zdroj: | JCI Insight. 4 |
| ISSN: | 2379-3708 |
| Popis: | Traumatic spinal cord injury (SCI) triggers an acute-phase response that leads to systemic inflammation and rapid mobilization of bone marrow (BM) neutrophils into the blood. These mobilized neutrophils then accumulate in visceral organs and the injured spinal cord where they cause inflammatory tissue damage. The receptor for complement activation product 3a, C3aR1, has been implicated in negatively regulating the BM neutrophil response to tissue injury. However, the mechanism via which C3aR1 controls BM neutrophil mobilization, and also its influence over SCI outcomes, are unknown. Here, we show that the C3a/C3aR1 axis exerts neuroprotection in SCI by acting as a physiological antagonist against neutrophil chemotactic signals. We show that C3aR1 engages phosphatase and tensin homolog (PTEN), a negative regulator of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, to restrain C-X-C chemokine receptor type 2-driven BM neutrophil mobilization following trauma. These findings are of direct clinical significance as lower circulating neutrophil numbers at presentation were identified as a marker for improved recovery in human SCI. Our work thus identifies C3aR1 and its downstream intermediary, PTEN, as therapeutic targets to broadly inhibit neutrophil mobilization/recruitment following tissue injury and reduce inflammatory pathology. |
| Databáze: | OpenAIRE |
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