MST4 attenuates NLRP3 inflammasome-mediated neuroinflammation and affects the prognosis after intracerebral hemorrhage in mice.

Abstract

BACKGROUND:

The kinase MST4 limits inflammatory responses through direct phosphorylation of the adaptor TRAF6. TRAF6 interacts with NLRP3 to promote the activation of NLRP3 inflammasome. However, the role of MST4 in neuroinflammation after intracerebral hemorrhage (ICH) and how it interacts with NLRP3 inflammasome remain unclear.

METHODS:

Mice were administered MST4 AAV four weeks before collagenase-induced ICH. ICH mice received either hesperadin (MST4 selective inhibitor), or MCC950 (NLRP3 inflammasome selective inhibitor). Neurological deficits and brain water content were assessed. Western blot and immunofluorescence were performed to evaluate the proteins content and localization in MST4/NLRP3 signaling pathway.

RESULTS:

The expression of endogenous MST4 and NLRP3 was increased after ICH compared to sham group. MST4 and NLRP3 were respectively colocalized in microglia. Upregulation of MST4 gene inhibited the activation of NLRP3 inflammasome, the release of IL-1β and TNF-α, and significantly improved brain edema and neurological deficits. Hesperadin pretreatment inhibited the expression of MST4 and increased the expression of NLRP3 inflammasome-mediated proteins, which aggravated neurological deficits and cerebral edema. MCC950 markedly alleviated neurological deficits and brain edema but had no effect on the expression of MST4 protein.

CONCLUSIONS:

MST4 alleviates inflammatory progression and brain injury in ICH mice possibly by inhibiting NLRP3 inflammasome activation.

• Authors: Xiaodong Wu, Yan Zhang, Yulong Zhang, Lei Xia, Yating Yang, Ping Wang, Yang Xu, Zhenhua Ren, Huanzhong Liu
• Journal: Brain research bulletin (Brain Res Bull) Vol. 177 Pg. 31-38 (12 2021) ISSN: 1873-2747 [Electronic] United States
• PMID: 34534636 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Inflammasomes
• NLR Family, Pyrin Domain-Containing 3 Protein
• Nlrp3 protein, mouse
• Stk26 protein, mouse
• Protein Serine-Threonine Kinases

Topics

• Animals
• Cerebral Hemorrhage (drug therapy, metabolism)
• Inflammasomes (metabolism)
• Mice
• NLR Family, Pyrin Domain-Containing 3 Protein (metabolism)
• Neuroinflammatory Diseases
• Prognosis
• Protein Serine-Threonine Kinases