2. Academic Validation
  3. The Src1-PGC1α-AP1 complex-dependent secretion of substance P induces inflammation and apoptosis in encephalomyocarditis virus-infected mice

The Src1-PGC1α-AP1 complex-dependent secretion of substance P induces inflammation and apoptosis in encephalomyocarditis virus-infected mice

  • Cytokine. 2023 Mar 27;165:156186. doi: 10.1016/j.cyto.2023.156186.
Fa-Xiu Chen 1,  Qin Wan 1,  Jing Fang 1,  Le Peng 1,  Qing-Ling Li 2,  Jian Hu 3
Affiliations

Affiliations

  • 1 Department of Geriatrics, The First Affiliated Hospital of Nanchang Medical College, Nanchang 330006, Jiangxi, China; Department of Geriatrics, Jiangxi Provincial People's Hospital, Nanchang 330006, Jiangxi, China.
  • 2 Department of Geriatrics, The First Affiliated Hospital of Nanchang Medical College, Nanchang 330006, Jiangxi, China; Department of Geriatrics, Jiangxi Provincial People's Hospital, Nanchang 330006, Jiangxi, China. Electronic address: [email protected].
  • 3 Department of Geriatrics, The First Affiliated Hospital of Nanchang Medical College, Nanchang 330006, Jiangxi, China; Department of Geriatrics, Jiangxi Provincial People's Hospital, Nanchang 330006, Jiangxi, China. Electronic address: [email protected].
PMID: 36989655 DOI: 10.1016/j.cyto.2023.156186
Abstract

Substance P (SP), a neuropeptide consisting of 11 amino acid residues, is involved in the pathogenesis of encephalomyocarditis virus (EMCV)-induced myocarditis by stimulating the production of proinflammatory cytokines. However, the underlying mechanism that regulates SP production is still unknown. In this study, we report the transcriptional regulation of the Tachykinin Precursor 1 (TAC1) gene that encodes SP by a transcriptional complex composed of Steroid Receptor Coactivator 1 (Src1), Peroxisome proliferator-activated receptor-gamma coactivator 1 (PGC1α), and Activator Protein 1 (AP1) transcription factor. Infection of mice with EMCV induced the accumulation of PGC1α and increased TAC1 expression, thereby promoting the secretion of SP, initiating Apoptosis, and elevating proinflammatory cytokine levels. In vitro overexpression of the Src1-PGC1α-AP1 members also induced TAC1 expression, increased the SP concentration, initiated Apoptosis, and elevated proinflammatory cytokine concentrations. Depletion or inhibition of the Src1-PGC1α-AP1 complex reversed these effects. The administration of gossypol, an Src1 inhibitor, or SR1892, a PGC1α inhibitor, to EMCV-infected mice attenuated myocarditis. Taken together, our results reveal that the upregulation of TAC1 and the secretion of SP in EMCV-induced myocarditis are dependent on the Src1-PGC1α-AP1 complex. Targeting the Src1-PGC1α-AP1 complex may represent a new therapeutic strategy for myocarditis.

Keywords

AP1; Myocarditis; PGC1α; Src1; Substance P.

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