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Schematic diagram of mechanism for anti-inflammatory action of C5aR antagonists (W54011). Complement and Toll-like receptors 4 (TLR4) are co-activated in response to lipopolysaccharide (LPS). During the activation of the complement cascade, C5 may be cleaved into its active products C5a. The C5a activation fragments activate its receptor C5aR. C5a binds to C5aR and crosstalk with TLR4 signaling. This synergy leads to enhancing the activation of downstream signaling pathways NF-κB and MAPK, such as NF-κB and activator protein 1 (AP-1), resulting in upregulating the expression of inflammatory factors (IL-1β, TNF-α, IL-6). C5aR antagonist can inhibited the C5a-C5aR signaling axi. Additionally, the C5aR antagonist eliminated complement-TLR4 crosstalk signaling, down-regulated the expression of TLR4, inhibited the phosphorylation of IκBα and JNK, and reduced the expression of p-P65 and p-JUN, to defend against inflammation.