Extracellular ASC exacerbated the recurrent ischemic stroke in an NLRP3-dependent manner


He Xiao-fei1,Zeng Yi-xuan2,Li Ge3,Feng Yu-kun4,Wu Cheng5,Liang Feng-yin1,Zhang Yu3,Lan Yue56,Xu Guang-qing78,Pei Zhong1


1. Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China

2. Department of Neurology, Shenzhen 2nd People's Hospital, The First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen, Guangdong, China

3. Guangdong Provincial Key Labortory of Labortory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, China

4. Department of Neurology, The Fifth Affiliated Hospital, Sun Yat-sen University, Zhuhai, China

5. Department of Rehabilitation Medicine, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China

6. Department of Rehabilitation Medicine, The Second Affiliated Hospital of South China University of Technology, Guangzhou, China

7. Department of Rehabilitation Medicine, Beijing Tiantan Hospital, Capital Medical University, Beijing, China

8. China National Clinical Research Center for Neurological Diseases, Beijing, China


Using a photothrombotic mouse model of single stroke, we show that a single stroke onset increases the nuclear factor-κB (NF-κB), NLR family CARD domain containing protein 4 (NLRC4), and absent in melanoma 2 (AIM2) inflammasomes, as well as the mRNA levels of NLRP3. Next, using a photothrombotic mouse model of recurrent stroke, we found that recurrent strokes increased the activation of NLRP3, exacerbated the brain damage and the pro-inflammatory response in wild type (WT) mice, but not in NLRP3 knockout ( NLRP3 KO) mice. Additionally, we found that apoptosis-associated speck-like protein containing a CARD (ASC) protein level surrounding the infarct area was comparatively increased, but that ASC specks outside of microglia in both the ipsilateral and contralateral of stroke site were decreased in NLRP3 KO mice relative to wild-type (WT) controls, and the number of ASC specks surrounding the second infarct area was positively correlated to the damage scores. Mechanistically, we found that recombinant ASC (RecASC) activated NLRP3 and induced pro-inflammatory responses, exacerbating the outcome of ischemic stroke, in WT mice, but not in NLRP3 KO mice. We therefore conclude that the NLRP3 inflammasome is activated by two attacks of stroke, which act together with ASC to exacerbate recurrent strokes.


SAGE Publications


Cardiology and Cardiovascular Medicine,Clinical Neurology,Neurology








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