Cpb1–C3–C3aR pathway increases p38 MAPK phosphorylation downstream of TLR4 and Ifnar activation in a cell autonomous and non–cell autonomous manner. WT, C3aR^−/−, and C3^−/− BMDMs were treated with (A) IFN-β or (B) IFN-γ for 2 h and the relative expression of caspase-11 and NOS2 transcripts were calculated via qRT-PCR, compared with GAPDH expression. (C) WT or C3aR^−/− BMDMs were treated with LPS, IFN-β, or IFN-γ for 2 h and lysed for analysis of p38-phosphorylation and β-actin was evaluated via Western blot. (D) WT, Cpb1 KO, or C3aR KO RAW macrophages were treated with LPS for 2 h and supernatants were added to naive Cpb1 KO cells for 2 h. The relative expression of caspase-11, il-6, and tnf-α were calculated via qRT-PCR, compared with GAPDH expression. Statistics were analyzed via the unpaired Student’s t test. *, P < 0.05; ***, P < 0.001; ****, P < 0.0001. Data are representative of at least two (D) or three (A–C) independent experiments, with three technical replicates each time.