PMID- 37660839
OWN - NLM
STAT- MEDLINE
DCOM- 20231102
LR  - 20231102
IS  - 1873-4596 (Electronic)
IS  - 0891-5849 (Linking)
VI  - 208
DP  - 2023 Nov 1
TI  - Macrophage CAPN4 regulates CVB3-induced cardiac inflammation and injury by 
      promoting NLRP3 inflammasome activation and phenotypic transformation to the 
      inflammatory subtype.
PG  - 430-444
LID - S0891-5849(23)00612-3 [pii]
LID - 10.1016/j.freeradbiomed.2023.08.032 [doi]
AB  - Exploring the immune mechanism of coxsackievirus B3 (CVB3)-induced myocarditis 
      may provide a promising therapeutic strategy. Here, we investigated the 
      regulatory role of macrophage CAPN4 in the phenotypic transformation of 
      macrophages and NOD-like receptor protein 3 (NLRP3) inflammasome activation. We 
      found that CAPN4 was the most upregulated subtype of the calpain family in 
      CVB3-infected bone marrow-derived macrophages (BMDMs) and Raw 264.7 cells after 
      CVB3 infection and was upregulated in cardiac macrophages from CVB3-infected 
      mice. Conditional knockout of CAPN4 (CAPN4(flox/flox); LYZ2-Cre, CAPN4-cKO mice) 
      ameliorated inflammation and myocardial injury and improved cardiac function and 
      survival after CVB3 infection. Enrichment analysis revealed that macrophage 
      differentiation and the interleukin signaling pathway were the most predominant 
      biological processes in macrophages after CVB3 infection. We further found that 
      CVB3 infection and the overexpression of CAPN4 promoted macrophage M1 
      polarization and NLRP3 inflammasome activation, while CAPN4 knockdown reversed 
      these changes. Correspondingly, CAPN4-cKO alleviated CVB3-induced M1 macrophage 
      transformation and NLRP3 expression and moderately increased M2 transformation in 
      vivo. The culture supernatant of CAPN4-overexpressing or CVB3-infected 
      macrophages impaired cardiac fibroblast function and viability. Moreover, 
      macrophage CAPN4 could upregulate C/EBP-homologous protein (chop) expression, 
      which increased proinflammatory cytokine release by activating the 
      phosphorylation of transducer of activator of transcription 1 (STAT1) and 3 
      (STAT3). Overall, these results suggest that CAPN4 increases M1-type and inhibits 
      M2-type macrophage polarization through the chop-STAT1/STAT3 signaling pathway to 
      mediate CVB3-induced myocardial inflammation and injury. CAPN4 may be a novel 
      target for viral myocarditis treatment.
CI  - Copyright (c) 2023 The Authors. Published by Elsevier Inc. All rights reserved.
FAU - Wang, Yucheng
AU  - Wang Y
AD  - Key Laboratory of Viral Cardiovascular Diseases, Ministry of Health, China & 
      Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, 
      Zhongshan Hospital, Shanghai Medical College of Fudan University, Xuhui District, 
      Shanghai, 200010, China.
FAU - Li, Minghui
AU  - Li M
AD  - Key Laboratory of Viral Cardiovascular Diseases, Ministry of Health, China & 
      Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, 
      Zhongshan Hospital, Shanghai Medical College of Fudan University, Xuhui District, 
      Shanghai, 200010, China.
FAU - Chen, Jun
AU  - Chen J
AD  - The Third Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 
      310000, Zhejiang, China.
FAU - Yu, Ying
AU  - Yu Y
AD  - Department of General Practice, Zhongshan Hospital, Shanghai Medical College of 
      Fudan University, Xuhui District, Shanghai, 200010, China.
FAU - Yu, Yong
AU  - Yu Y
AD  - Key Laboratory of Viral Cardiovascular Diseases, Ministry of Health, China & 
      Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, 
      Zhongshan Hospital, Shanghai Medical College of Fudan University, Xuhui District, 
      Shanghai, 200010, China.
FAU - Shi, Hui
AU  - Shi H
AD  - Key Laboratory of Viral Cardiovascular Diseases, Ministry of Health, China & 
      Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, 
      Zhongshan Hospital, Shanghai Medical College of Fudan University, Xuhui District, 
      Shanghai, 200010, China.
FAU - Liu, Xiaoxiao
AU  - Liu X
AD  - Key Laboratory of Viral Cardiovascular Diseases, Ministry of Health, China & 
      Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, 
      Zhongshan Hospital, Shanghai Medical College of Fudan University, Xuhui District, 
      Shanghai, 200010, China.
FAU - Chen, Zhiwei
AU  - Chen Z
AD  - Key Laboratory of Viral Cardiovascular Diseases, Ministry of Health, China & 
      Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, 
      Zhongshan Hospital, Shanghai Medical College of Fudan University, Xuhui District, 
      Shanghai, 200010, China.
FAU - Chen, Ruizhen
AU  - Chen R
AD  - Key Laboratory of Viral Cardiovascular Diseases, Ministry of Health, China & 
      Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, 
      Zhongshan Hospital, Shanghai Medical College of Fudan University, Xuhui District, 
      Shanghai, 200010, China. Electronic address: chen.ruizhen@zs-hospital.sh.cn.
FAU - Ge, Junbo
AU  - Ge J
AD  - Key Laboratory of Viral Cardiovascular Diseases, Ministry of Health, China & 
      Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, 
      Zhongshan Hospital, Shanghai Medical College of Fudan University, Xuhui District, 
      Shanghai, 200010, China.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20230901
PL  - United States
TA  - Free Radic Biol Med
JT  - Free radical biology & medicine
JID - 8709159
RN  - 0 (Inflammasomes)
RN  - 0 (NLR Family, Pyrin Domain-Containing 3 Protein)
RN  - 0 (NLR Proteins)
SB  - IM
MH  - Animals
MH  - Mice
MH  - *Coxsackievirus Infections/genetics/metabolism
MH  - Enterovirus B, Human/metabolism
MH  - *Inflammasomes/metabolism
MH  - Inflammation/genetics/metabolism
MH  - Macrophages/metabolism
MH  - *Myocarditis/genetics/metabolism
MH  - NLR Family, Pyrin Domain-Containing 3 Protein/genetics/metabolism
MH  - NLR Proteins/metabolism
OTO - NOTNLM
OT  - Calpain
OT  - Chop
OT  - Macrophage polarization
OT  - NLRP3 inflammasome
OT  - Viral myocarditis
COIS- Declaration of competing interest The authors declare that they have no known 
      competing financial interests or personal relationships that could have appeared 
      to influence the work reported in this paper.
EDAT- 2023/09/04 00:41
MHDA- 2023/10/23 00:43
CRDT- 2023/09/03 19:26
PHST- 2023/06/26 00:00 [received]
PHST- 2023/08/31 00:00 [revised]
PHST- 2023/08/31 00:00 [accepted]
PHST- 2023/10/23 00:43 [medline]
PHST- 2023/09/04 00:41 [pubmed]
PHST- 2023/09/03 19:26 [entrez]
AID - S0891-5849(23)00612-3 [pii]
AID - 10.1016/j.freeradbiomed.2023.08.032 [doi]
PST - ppublish
SO  - Free Radic Biol Med. 2023 Nov 1;208:430-444. doi: 
      10.1016/j.freeradbiomed.2023.08.032. Epub 2023 Sep 1.