Inhibition of the interaction between microglial adenosine 2A receptor and NLRP3 inflammasome attenuates neuroinflammation posttraumatic brain injury

Abstract

AimsAdenosine 2A receptor (A2AR) is widely expressed in the brain and plays important roles in neuroinflammation, and the nucleotide‐binding oligomerization domain, leucine‐rich repeat, and pyrin domain‐containing protein 3 (NLRP3) inflammasome is a crucial component of the innate immune system while the regulation of A2AR on it in the central nervous system (CNS) has not been clarified.MethodsThe effects of microglial A2AR on NLRP3 inflammasome assembly and activation were investigated in wild‐type, A2AR‐ or NLRP3‐knockout primary microglia with pharmacological treatment. Microglial A2AR or NLRP3 conditional knockout mice were used to interrogate the effects of this regulation on neuroinflammation posttraumatic brain injury (TBI).ResultsWe found that A2AR directly interacted with NLRP3 and facilitated NLRP3 inflammasome assembly and activation in primary microglia while having no effects on mRNA levels of inflammasome components. Inhibition of the interaction via A2AR agonist or knockout attenuated inflammasome assembly and activation in vitro. In the TBI model, microglial A2AR and NLRP3 were co‐expressed at high levels in microglia next to the peri‐injured cortex, and abrogating of this interaction by microglial NLRP3 or A2AR conditional knockout attenuated the neurological deficits and neuropathology post‐TBI via reducing the NLRP3 inflammasome activation.ConclusionOur results demonstrated that inhibition of the interaction between A2AR and NLRP3 in microglia could mitigate the NLRP3 inflammasome assembly and activation and ameliorate the neuroinflammation post‐TBI. It provides new insights into the effects of A2AR on neuroinflammation regulation post‐TBI and offers a potential target for the treatment of NLRP3 inflammasome‐related CNS diseases.

HuR deficiency abrogated the enhanced NLRP3 signaling in experimental ischemic stroke

“…The Nod-like receptor protein 3 (NLRP3) inflammasome has emerged as a crucial mediator of neuroinflammation. 13 Upon activation, the NLRP3 inflammasome can activate caspase-1 (casp-1), which in turn cleaves and activates proinflammatory cytokines, leading to the recruitment and activation of immune cells, exacerbating the inflammatory response and promoting tissue damage. 14 In our previous study, we found that NLRP3 can aggravate the degree of CIRI in mice through the activation of inflammasome pathway.…”