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Complement receptor C3aR1 controls neutrophil mobilization following spinal cord injury through physiological antagonism of CXCR2.
- Source :
-
JCI insight [JCI Insight] 2019 May 02; Vol. 4 (9). Date of Electronic Publication: 2019 May 02 (Print Publication: 2019). - Publication Year :
- 2019
-
Abstract
- 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.
- Subjects :
- Adult
Animals
Bone Marrow pathology
Cell Adhesion
Cell Movement
Disease Models, Animal
Female
Humans
Inflammation
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Neutrophil Infiltration
PTEN Phosphohydrolase metabolism
Phosphatidylinositol 3-Kinases
Receptor, Anaphylatoxin C5a genetics
Spinal Cord Injuries pathology
Transcriptome
Wounds and Injuries pathology
Young Adult
Neutrophils metabolism
Receptors, Complement genetics
Receptors, Complement metabolism
Receptors, Interleukin-8B metabolism
Spinal Cord Injuries metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2379-3708
- Volume :
- 4
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- JCI insight
- Publication Type :
- Academic Journal
- Accession number :
- 31045582
- Full Text :
- https://doi.org/10.1172/jci.insight.98254