Model of Cpb1–C3–C3aR pathway amplifying p38 MAPK signaling downstream of TLR4 and Ifnar activation in macrophages. TLR4 and Ifnar activation through their respective ligands induce expression of proinflammatory genes via various mechanisms, including the induction of p38 MAPK (Lee et al., 1994; Sancéau et al., 2000). C3 expression is induced downstream these pathways (Riches et al., 1988; Maranto et al., 2011), and is quickly released from macrophages (Goodrum, 1987), where it is cleaved into C3a and C3b. Anaphylotoxin C3a can be cleaved extracellularly by Cpb1 into C3a-desArg (Leung et al., 2008; Chatterjee et al., 2009), where it then acts as a ligand for C3aR. We find, the activation of C3aR then amplifies MAPK activity through enhancing p38 MAPK phosphorylation downstream of TLR4 and Ifnar, but not Ifngr, activation. Due to the extracellular nature of this signaling pathway, the Cpb1–C3–C3aR pathway acts as a cell-autonomous and a non–cell autonomous amplification pathway enhancing expression of proinflammatory genes of self- and neighboring macrophages.