PMID- 35902863
OWN - NLM
STAT- MEDLINE
DCOM- 20220801
LR  - 20220803
IS  - 1742-2094 (Electronic)
IS  - 1742-2094 (Linking)
VI  - 19
IP  - 1
DP  - 2022 Jul 28
TI  - Transforming growth factor-beta1 protects against LPC-induced cognitive deficit by 
      attenuating pyroptosis of microglia via NF-kappaB/ERK1/2 pathways.
PG  - 194
LID - 10.1186/s12974-022-02557-0 [doi]
LID - 194
AB  - BACKGROUND: Demyelinating diseases in central nervous system (CNS) are a group of 
      diseases characterized by myelin damage or myelin loss. Transforming growth 
      factor beta1 (TGF-beta1) is widely recognized as an anti-inflammatory cytokine, 
      which can be produced by both glial and neuronal cells in CNS. However, the 
      effects of TGF-beta1 on demyelinating diseases and its underlying mechanisms have 
      not been well investigated. METHODS: A demyelinating mouse model using two-point 
      injection of lysophosphatidylcholine (LPC) to the corpus callosum in vivo was 
      established. Exogenous TGF-beta1 was delivered to the lesion via brain stereotactic 
      injection. LFB staining, immunofluorescence, and Western blot were applied to 
      examine the severity of demyelination and pyroptosis process in microglia. Morris 
      water maze test was used to assess the cognitive abilities of experimental mice. 
      Furthermore, lipopolysaccharide (LPS) was applied to induce pyroptosis in primary 
      cultured microglia in vitro, to explore potential molecular mechanism. RESULTS: 
      The degree of demyelination in LPC-modeling mice was found improved with 
      supplement of TGF-beta1. Besides, TGF-beta1 treatment evidently ameliorated the 
      activated proinflammatory pyroptosis of microglia, with downregulated levels of 
      the key pyroptosis effector Gasdermin D (GSDMD), inflammasomes, and 
      cleaved-IL-1beta, which effectively attenuated neuroinflammation in vivo. Evaluated 
      by behavioral tests, the cognitive deficit in LPC-modeling mice was found 
      mitigated with application of TGF-beta1. Mechanistically, TGF-beta1 could reverse 
      pyroptosis-like morphology in LPS-stimulated primary cultured microglia observed 
      by scanning electron microscopy, as well as decrease the protein levels of 
      cleaved-GSDMD, inflammasomes, and cleaved-IL-1beta. Activation of ERK1/2 and NF-kappaB 
      pathways largely abolished the protective effects of TGF-beta1, which indicated that 
      TGF-beta1 alleviated the pyroptosis possibly via regulating NF-kappaB/ERK1/2 signal 
      pathways. CONCLUSIONS: Our studies demonstrated TGF-beta1 notably relieved the 
      demyelinating injury and cognitive disorder in LPC-modeling mice, by attenuating 
      the inflammatory pyroptosis of microglia via ERK1/2 and NF-kappaB pathways. Targeting 
      TGF-beta1 activity might serve as a promising therapeutic strategy in demyelinating 
      diseases.
CI  - (c) 2022. The Author(s).
FAU - Xie, Yi
AU  - Xie Y
AD  - Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, 430030, China.
FAU - Chen, Xuejiao
AU  - Chen X
AD  - Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, 430030, China.
FAU - Li, Ying
AU  - Li Y
AD  - Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, 430030, China.
FAU - Chen, Simiao
AU  - Chen S
AD  - Department of Rehabilitation Medicine, The First Affiliated Hospital of Medical 
      College, Zhejiang University, Hangzhou, 310003, China.
FAU - Liu, Shuai
AU  - Liu S
AD  - Reproductive Medicine Center, Tongji Hospital, Tongji Medicine College, Huazhong 
      University of Science and Technology, Wuhan, 430030, China.
FAU - Yu, Zhiyuan
AU  - Yu Z
AD  - Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, 430030, China.
FAU - Wang, Wei
AU  - Wang W
AD  - Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong 
      University of Science and Technology, Wuhan, 430030, China. wwang@vip.126.com.
LA  - eng
GR  - 82171385/National Natural Science Foundation of China/
GR  - 61327902-6/National Natural Science Foundation of China/
GR  - 2020YFC0861000/National Key Research and Development Program of China/
PT  - Journal Article
DEP - 20220728
PL  - England
TA  - J Neuroinflammation
JT  - Journal of neuroinflammation
JID - 101222974
RN  - 0 (Inflammasomes)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Lysophosphatidylcholines)
RN  - 0 (NF-kappa B)
RN  - 0 (Transforming Growth Factor beta1)
SB  - IM
MH  - Animals
MH  - Cognition
MH  - *Demyelinating Diseases/pathology
MH  - Inflammasomes/metabolism
MH  - Lipopolysaccharides/pharmacology
MH  - Lysophosphatidylcholines/toxicity
MH  - MAP Kinase Signaling System/physiology
MH  - Mice
MH  - Microglia/metabolism
MH  - *NF-kappa B/metabolism
MH  - Pyroptosis/physiology
MH  - Transforming Growth Factor beta1/metabolism
PMC - PMC9336072
OTO - NOTNLM
OT  - Cognitive deficit
OT  - Demyelination
OT  - LPC
OT  - Microglia
OT  - Neuroinflammation
OT  - Pyroptosis
OT  - TGF-beta1
COIS- The authors declare that they have no competing interests.
EDAT- 2022/07/29 06:00
MHDA- 2022/08/02 06:00
PMCR- 2022/07/28
CRDT- 2022/07/28 23:48
PHST- 2022/04/04 00:00 [received]
PHST- 2022/07/06 00:00 [accepted]
PHST- 2022/07/28 23:48 [entrez]
PHST- 2022/07/29 06:00 [pubmed]
PHST- 2022/08/02 06:00 [medline]
PHST- 2022/07/28 00:00 [pmc-release]
AID - 10.1186/s12974-022-02557-0 [pii]
AID - 2557 [pii]
AID - 10.1186/s12974-022-02557-0 [doi]
PST - epublish
SO  - J Neuroinflammation. 2022 Jul 28;19(1):194. doi: 10.1186/s12974-022-02557-0.