C5aR1 mediates progression of inflammatory responses in brain of rats
after ischemia and reperfusion
Abstract
C5a receptor 1 (C5aR1) can induce strong inflammatory response to
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 determine whether C5aR1 signaling is
essential to the development of post-ischemic inflammation and brain
injury and whether it is a valid target for therapeutic blockade with
soluble receptor antagonist PMX53. 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, neuronal
cells of rats showed significantly up-regulated gene expression of
C5aR1, and notable inflammatory response 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. The further
mechanism studies showed that inhibiting C5aR1 by PMX53 protected rats
from MCAO/R injury, decreased cell inflammation and apoptosis via
inhibiting 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
cascades 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.