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

Aims: Adenosine 2A receptor (A R) 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 A R on it in the central nervous system (CNS) has not been clarified.

Methods: The effects of microglial A R on NLRP3 inflammasome assembly and activation were investigated in wild-type, A R- or NLRP3-knockout primary microglia with pharmacological treatment. Microglial A R or NLRP3 conditional knockout mice were used to interrogate the effects of this regulation on neuroinflammation posttraumatic brain injury (TBI).

Ablation of GSDMD Attenuates Neurological Deficits and Neuropathological Alterations After Traumatic Brain Injury.

Pyroptosis plays a significant role in neuroinflammation after traumatic brain injury (TBI). However, the role of pyroptosis executor Gasdermin D (GSDMD) in neurological deficits and neuropathological alterations after TBI have not been elucidated. Our results demonstrated that GSDMD-KO exerted striking neuroprotective effects on motor dysfunction and neuropathological alterations (loss of synaptic proteins, microglia activation, astrogliosis, dendrite injury, and neuron death) at 3 days after TBI.

High glutamate concentration reverses the inhibitory effect of microglial adenosine 2A receptor on NLRP3 inflammasome assembly and activation.

NLRP3 inflammasome plays a crucial role in the innate immune system. Our group previously reported that the microglial adenosine 2A receptor (AR) regulates canonical neuroinflammation, which is affected by the glutamate concentration. However, the regulatory effect of AR on NLRP3 inflammasome and the effects of glutamate concentration remain unknown.