The receptor for complement component C3a mediates protection from intestinal ischemia-reperfusion injuries by inhibiting neutrophil mobilization

Abstract

C3a is a key complement activation fragment, yet its neutrophil-expressed receptor (C3aR) still has no clearly defined role. In this study, we used a neutrophil-dependent mouse model of intestinal ischemia-reperfusion (IR) injury to explore the role of C3aR in acute tissue injuries. C3aR deficiency worsened intestinal injury, which corresponded with increased numbers of tissue-infiltrating neutrophils. Circulating neutrophils were significantly increased in C3aR −/− mice after intestinal ischemia, and C3aR −/− mice also mobilized more circulating neutrophils after granulocyte colony-stimulating factor infusion compared with WT mice, indicating a specific role for C3aR in constraining neutrophil mobilization in response to intestinal injury. In support of this role, C3aR −/− mice reconstituted with WT bone marrow reversed IR pathology back to WT levels. Complement C5a receptor (C5aR) antagonism in C3aR −/− mice also rectified the worsened pathology after intestinal IR injury but had no effect on circulating neutrophils, highlighting the opposing roles of C3a and C5a in disease pathogenesis. Finally, we found that using a potent C3a agonist to activate C3aR in vivo reduced neutrophil mobilization and ameliorated intestinal IR pathology in WT, but not C3aR −/− , mice. This study identifies a role for C3aR in regulating neutrophil mobilization after acute intestinal injury and highlights C3aR agonism as a potential treatment option for acute, neutrophil-driven pathologies.

Is the Complement Activation Product C3a a Proinflammatory Molecule? Re-evaluating the Evidence and the Myth

“…The role for C5a in the progression of this pathology is both very well understood and unambiguous; C5a functions at the level of injury to cause extravasation and degranulation of the circulating neutrophils (55). By direct contrast, we demonstrated in a model of intestinal IR that the role for C3a in this acute pathology is overwhelmingly anti-inflammatory (32). Thus, the historical model for C3a as being a "weaker" form of C5a as a proinflammatory mediator is no longer uncomplicated.…”

“…Interestingly, the signaling produced by C3a stimulation of neutrophils was shown in one report to be dependent on the presence of C5aR2, suggesting that C5aR2 may contribute to C3a signaling through interactions with C3aR (34). However, our recent studies indicate that, at the level of the bone marrow, C3a prevents migration of neutrophils into the circulation by acting in direct opposition to neutrophil-mobilizing factors, such as G-CSF, in a manner reminiscent of stromal cell-derived factor-1 (32).…”

“…2). For example, despite a canonical proinflammatory histamine degranulation response for C3a on mast cells (31), our laboratory recently showed a potent anti-inflammatory response for C3a on neutrophils, by attenuating their mobilization into the circulation following injury (32). Uninhibited mobilization can FIGURE 1.…”

“…C3a levels in both blood and intestinal tissues increase after a period of ischemia, likely from activation of the complement system in response to damage-associated molecular patterns (32). Additionally, at the site of acute inflammation, carboxypeptidases preferentially degrade C5a over C3a, perhaps allowing for C3a to escape degradation and exert systemic actions (8).…”

Radiotherapy: killing with complement

“…However, use of inhibitors is always limited by the specificity of the treatment. For example, the C3aR antagonist SB290157 also exhibits agonist activity and may stimulate C3aR and mobilize neutrophils in intestinal ischemia reperfusion injury (15,16). Literature reported doses of SB290157 range from 2-30 mg/kg with minimal data indicating that these doses are C3aR specific and lack off target effects.…”