Complement receptor C3aR1 controls neutrophil mobilization following spinal cord injury through physiological antagonism of CXCR2
Faith H. Brennan, Trisha Jogia, Ellen R. Gillespie, Linda V. Blomster, Xaria X. Li, Bianca Nowlan, Gail M. Williams, Esther Jacobson, Geoff W. Osborne, Frederic A. Meunier, Stephen M. Taylor, Kate E. Campbell, Kelli P.A. MacDonald, Jean-Pierre Levesque, Trent M. Woodruff, Marc J. Ruitenberg
Faith H. Brennan, Trisha Jogia, Ellen R. Gillespie, Linda V. Blomster, Xaria X. Li, Bianca Nowlan, Gail M. Williams, Esther Jacobson, Geoff W. Osborne, Frederic A. Meunier, Stephen M. Taylor, Kate E. Campbell, Kelli P.A. MacDonald, Jean-Pierre Levesque, Trent M. Woodruff, Marc J. Ruitenberg
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Research Article Inflammation Neuroscience

Complement receptor C3aR1 controls neutrophil mobilization following spinal cord injury through physiological antagonism of CXCR2

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.

Authors

Faith H. Brennan, Trisha Jogia, Ellen R. Gillespie, Linda V. Blomster, Xaria X. Li, Bianca Nowlan, Gail M. Williams, Esther Jacobson, Geoff W. Osborne, Frederic A. Meunier, Stephen M. Taylor, Kate E. Campbell, Kelli P.A. MacDonald, Jean-Pierre Levesque, Trent M. Woodruff, Marc J. Ruitenberg

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Figure 2

Neurological recovery from SCI is impaired in absence of C3aR1.

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Neurological recovery from SCI is impaired in absence of C3aR1. (A) Open...
(A) Open field locomotor (BMS) scores, showing the recovery of comparably injured WT and C3ar1–/– mice. Note that C3ar1–/– mice regained less hindlimb locomotor function and had significantly lower BMS scores at 14, 21, 28, and 35 days after SCI. Data points represent mean ± SEM (n = 13–15). *P < 0.05; **P < 0.01 by 2-way repeated-measures ANOVA with Bonferroni’s post hoc test (WT vs. C3ar1–/– mice at matching time points). (B) Bar graph showing endpoint BMS scores (mean ± SEM), with data points representing individual mice within each cohort (n = 13–15). ***P < 0.001 by 2-tailed Student’s t test. (C) Representative images showing postmortem T2*-weighted spinal cord MRIs for WT and C3ar1–/– mice at 35 days after injury. (D) Quantitative analysis of hypointense lesion core volumes (voxels) in WT and C3ar1–/– mice (n = 5 per group); representative 3D reconstructions of lesion cores are shown at the top of the graph for each genotype. **P < 0.01 by 2-tailed Student’s t test. (E) Representative images of the lesion epicenter in WT and C3ar1–/– mice at 35 days after SCI, showing myelin staining (red, left), GFAP immunoreactivity (green, middle), and a merged image (right). (F and G) Quantitative analysis showing decreased myelin content (F) but no difference in GFAP staining (G) at the lesion epicenter in C3arR1–/– mice. **P < 0.01 by 2-tailed Student’s t test. (H and I) Representative cresyl violet–stained sections and quantitative analysis showing an increased abnormal granular tissue presence in lesioned C3ar1–/– spinal cord. **P < 0.01 by 2-tailed Student’s t test. Scale bars: 0.75 mm (sagittal) or 0.4 mm (coronal) (C), 50 μm (D), 250 μm (E), and 300 μm (H).