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 3

C3ar1–/– mice have increased neutrophil recruitment and display acute granulocytosis in response to SCI.

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C3ar1–/– mice have increased neutrophil recruitment and display acute g...
(A) Photomicrographs (left) and quantitative data (right) of the Ly6B.2+ infiltrate in WT and C3ar1–/– mice. Dashed red lines indicate the boundary between the dorsal columns and horns (1 day after SCI). Note that Ly6B.2+ cell numbers are significantly increased in the injured spinal cord of C3ar1–/– mice at 1, 10, and 35 days after SCI. Data points represent the mean ± SEM (n = 5–8). Scale bar: 50 μm. (B) Quantitative analysis of circulating blood granulocyte numbers acutely after SCI. Note the significant expansion of this population in C3ar1–/– mice at 2 hours after SCI. (C) BM granulocyte numbers were significantly lower in C3ar1–/– mice at 2 hours after SCI compared with their WT counterparts. Data points for B and C are mean ± SEM (n = 6 per genotype and time point). *P < 0.05; **P < 0.01; ***P < 0.001 by 2-way ANOVA with Bonferroni’s post hoc test for matching time points.