C5aR1 Mediates the Progression of Inflammatory Responses in the Brain of Rats in the Early Stage after Ischemia and Reperfusion

Abstract

C5a receptor 1 (C5aR1) can induce a strong inflammatory response to an injury. Targeting C5aR1 has emerged as a novel anti-inflammatory therapeutic method. However, the role of C5aR1 in cerebral ischemia and reperfusion (I/R) injury and the definitive mechanism have not been elucidated clearly. Here, we determined whether C5aR1 signaling was essential to the post-ischemic inflammation and brain injury and whether it is a valid target for therapeutic blockade by using soluble receptor antagonist PMX53 in the early stage after I/R injury. In an in vitro model (oxygen and glucose deprivation and reperfusion, OGD/R) and in vivo model (middle cerebral artery occlusion and reperfusion, MCAO/R) of I/R, the neuronal cells of rats showed significantly up-regulated gene expression of C5aR1, and a notable inflammatory response was demonstrated with elevated tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6. Inhibition of C5aR1 by PMX53 treatment significantly reduced cell injury and inflammation and promoted brain function recovery. Further mechanism studies showed that inhibiting C5aR1 by PMX53 protected the rats from MCAO/R injury, decreased cell inflammation, and apoptosis via inhibiting the TLR4 and NF-κB signaling pathway and reducing the production of TNF-α, IL-1β, and IL-6 in MCAO/R rats. In addition, manipulation of the C5aR1 gene expression in vitro displayed that the inflammatory cascade signals including TLR4, TNF-α, IL-1β, and IL-6 were coincidently regulated with the regulation of C5aR1 expression levels. Thus, our results demonstrated a pathogenic role for C5aR1 in the progression of brain injury and inflammation response following I/R injury. Our study clearly demonstrated that C5aR1 inhibition might be an effective treatment strategy for ischemic stroke.

Identification of cell death-related biomarkers and immune infiltration in ischemic stroke between male and female patients

“…C5A receptor 1 (C5AR1) induces a strong inflammatory response to injury. Rat neuronal cells in a model of cerebral ischemia and reperfusion (I/R) exhibit significant upregulation of C5aR1 gene expression, and inflammatory cascade signals, including TLR4, TNF-α, IL-1β, and IL-6, are regulated in parallel with the regulation of C5AR1 expression levels, demonstrating the pathogenic role of C5AR1 in the progression of brain injury and inflammatory response after I/R injury ( 42 ). The results of this study corroborated the function of C5AR1 as a gene that was elevated in IS.…”

The Complement System in the Central Nervous System: From Neurodevelopment to Neurodegeneration

“…PM53 and PM205 are both cyclic hexapeptides, acting as C5aR antagonists. Considering the protective effects observed from preclinical evidence, C5aR antagonists bear the potential to become clinical therapeutic agents [ 54 , 57 , 69 , 169 , 170 ].…”

Silenced-C5ar1 improved multiple organ injury in sepsis rats via inhibiting neutrophil extracellular trap

“…C5ar1 is a gene related to strong inflammatory reactions and is found to be associated with interleukin (IL)-6, IL-1β, tumor necrosis factor (TNF)-α, and other inflammatory factors (Shi et al 2021 ). A study found that inhibition of C5ar1 can antagonize NETs-induced thrombosis in vitro (Skendros et al 2020 ).…”