The Alternative C5a Receptor Function

Abstract

When acute inflammatory states are induced by treatment with chemical mediators in C5-deficient mice, neutrophil influxes are commonly decreased. Therefore, the neutrophil C5a receptor (C5aR) is believed to be a member of the pro-inflammatory receptors. However, C5aR deficiency endows mouse neutrophils with increased sensitivity to Pseudomonas aeruginosa. We have demonstrated that C5aR accepts not only C5a but also ribosomal protein S19 (RP S19) oligomers. RP S19 oligomers released from apoptotic cells promote apoptosis or induce dual agonistic and antagonistic effects on the chemotaxis of macrophages and neutrophils in an autocrine or paracrine manner, respectively. We assumed that the function of C5aR in apoptotic cells is almost the same as that in neutrophils infiltrating acute inflammatory lesions. Therefore, we believe that RP S19 oligomers can explain the opposite response of neutrophils in C5aR-deficient mice. In the present study, we found that antihuman RP S19 rabbit IgG cross-reacted with mouse RP S19 monomers and oligomers in plasma and serum, respectively, whereas anti-human C5a rabbit IgG only cross-reacted with mouse RP S19 oligomers in serum. To examine a role of RP S19 oligomers in vivo, we injected carrageenan (50 microg/100 microL) into the thoracic cavities of mice in the simultaneous presence of rabbit IgG and antihuman C5a rabbit IgG (100 microg/100 microL). Before 4 h and after 24 h, we did not observe any inflammatory cues in pleural exudates and lung substances from control mice. However, infiltrating neutrophils were detected in pleural exudates and lung tissues at 4 h after the addition of anti-human RP S19 rabbit IgG. Moreover, anti-human C5a rabbit IgG retards the initiation phase of carrageenan-induced mouse plurality. Many of the neutrophils infiltrating the thoracic cavities of the mice remained annexin V-negative. Neutrophil infiltration into pneumonic lesions became more severe, as alveolar septal destruction and haemorrhage concomitant with increased numbers of neutrophils in the pleural exudates were observed. These in vivo data demonstrate that the neutrophil C5aR acts as a dual pro-inflammatory and pro-apoptosis receptor during the initiation and the resolution phases of acute inflammation, respectively.