Absence in CX3CR1 receptor signaling promotes post‐ischemic stroke cognitive function recovery through suppressed microglial pyroptosis in mice

Abstract

Background

Post‐stroke cognitive impairment (PSCI) is a major source of morbidity and mortality after stroke, but the pathological mechanisms remain unclear. Previous studies have demonstrated that the CX3CR1 receptor plays a crucial role in maintaining an early protective microenvironment after stroke, but whether it persistently influences cognitive dysfunction in the chronic phase requires further investigation.

Methods

Mouse was used to establish a middle cerebral artery occlusion (MCAO)/reperfusion model to study PSCI. Cognitive function was assessed by the Morris water maze (MWM) and the novel object recognition test. Neurogenesis was assessed by immunofluorescence staining with Nestin ⁺/Ki67 ⁺ and DCX ⁺/BrdU ⁺ double‐positive cells. The cerebral damage was monitored by [ ¹⁸F]‐DPA‐714 positron emission tomography, Nissel, and TTC staining. The pyroptosis was histologically, biochemically, and electron microscopically examined.

Results

Upon MCAO, at 28 to 35 days, CX3CR1 knockout (CX3CR1 ^−/−) mice had better cognitive behavioral performance both in MWM and novel object recognition test than their CX3CR1 ^+/− counterparts. Upon MCAO, at 7 days, CX3CR1 ^−/− mice increased the numbers of Nestin ⁺/Ki67 ⁺ and DCX ⁺/BrdU ⁺ cells, and meanwhile it decreased the protein expression of GSDMD, NLRP3 inflammasome subunit, caspase‐1, mature IL‐1β/IL‐18, and p‐P65 in the hippocampus as compared with CX3CR1 ^+/− mice. In addition, CX3CR1 ^−/− mice could reverse infarct volume in the hippocampus region post‐stroke.

Conclusion

Our study demonstrated that CX3CR1 gene deletion was beneficial to PSCI recovery. The mechanism might lie in inhibited pyroptosis and enhanced neurogenesis. CX3CR1 receptor may serve as a therapeutic target for improving the PSCI.

Abstract

Mice deficient in CX3CR1 receptor show improved post‐stroke cognitive impairment (PSCI). Mice deficient in the CX3CR1 receptor have inhibited the microglia pyroptosis‐induced neuroinflammation following ischemic stroke.