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Agmatine-IRF2BP2 interaction induces M2 phenotype of microglia by increasing IRF2-KLF4 signaling

Authors
 Jiwon Kim  ;  A Young Sim  ;  Sumit Barua  ;  Jong Youl Kim  ;  Jong Eun Lee 
Citation
 INFLAMMATION RESEARCH, Vol.72(6) : 1203-1213, 2023-06 
Journal Title
INFLAMMATION RESEARCH
ISSN
 1023-3830 
Issue Date
2023-06
MeSH
Agmatine* / metabolism ; Agmatine* / pharmacology ; Carrier Proteins / metabolism ; DNA-Binding Proteins ; Humans ; Inflammation / metabolism ; Interferon Regulatory Factor-2 / metabolism ; Interferon Regulatory Factor-2 / pharmacology ; Kruppel-Like Factor 4 ; Lipopolysaccharides / metabolism ; Lipopolysaccharides / pharmacology ; Microglia / metabolism ; Neuroinflammatory Diseases ; Phenotype ; Transcription Factors / metabolism
Keywords
Agmatine ; IRF2 ; IRF2BP2 ; KLF4 ; Microglia ; Neuroinflammation
Abstract
Background: Following central nervous system (CNS) injury, the investigation for neuroinflammation is vital because of its pleiotropic role in both acute injury and long-term recovery. Agmatine (Agm) is well known for its neuroprotective effects and anti-neuroinflammatory properties. However, Agm's mechanism for neuroprotection is still unclear. We screened target proteins that bind to Agm using a protein microarray; the results showed that Agm strongly binds to interferon regulatory factor 2 binding protein (IRF2BP2), which partakes in the inflammatory response. Based on these prior data, we attempted to elucidate the mechanism by which the combination of Agm and IRF2BP2 induces a neuroprotective phenotype of microglia.

Methods: To confirm the relationship between Agm and IRF2BP2 in neuroinflammation, we used microglia cell-line (BV2) and treated with lipopolysaccharide from Escherichia coli 0111:B4 (LPS; 20 ng/mL, 24 h) and interleukin (IL)-4 (20 ng/mL, 24 h). Although Agm bound to IRF2BP2, it failed to enhance IRF2BP2 expression in BV2. Therefore, we shifted our focus onto interferon regulatory factor 2 (IRF2), which is a transcription factor and interacts with IRF2BP2.

Results: IRF2 was highly expressed in BV2 after LPS treatment but not after IL-4 treatment. When Agm bound to IRF2BP2 following Agm treatment, the free IRF2 translocated to the nucleus of BV2. The translocated IRF2 activated the transcription of Kruppel-like factor 4 (KLF4), causing KLF4 to be induced in BV2. The expression of KLF4 increased the CD206-positive cells in BV2.

Conclusions: Taken together, unbound IRF2, resulting from the competitive binding of Agm to IRF2BP2, may provide neuroprotection against neuroinflammation via an anti-inflammatory mechanism of microglia involving the expression of KLF4.
Full Text
https://link.springer.com/article/10.1007/s00011-023-01741-z
DOI
10.1007/s00011-023-01741-z
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Anatomy (해부학교실) > 1. Journal Papers
Yonsei Authors
Kim, Jong Youl(김종열) ORCID logo https://orcid.org/0000-0002-8340-2894
Lee, Jong Eun(이종은) ORCID logo https://orcid.org/0000-0001-6203-7413
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/195502
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