The activation of CaN/NFAT signaling pathway in macrophages aggravated Lactobacillus casei cell wall extract-induced Kawasaki disease vasculitis

Cytokine. 2023 Sep:169:156304. doi: 10.1016/j.cyto.2023.156304. Epub 2023 Jul 22.

Abstract

Objectives: By using GWAS(genome-wide association studies) and linkage disequilibrium analysis to investigate the susceptibility genes of KD(Kawasaki disease), previous studies have identified that the CaN(calcineurin)-NFAT(the nuclear factor of activated T cell) signal pathway were significantly associated with susceptibility to KD. However, little is known about the molecular basis of the CaN/NFAT pathway involved in KD. Therefore, in our study we investigate the role of Ca2+/CaN/NFAT signaling pathway in macrophages in vitro and in vivo on coronary artery lesions induced by LCWE (Lactobacillus casei cell wall extract).

Methods and results: We observed that LCWE could increase the expression of NFAT1 and NFAT2 in macrophages in vitro, and also enhance the transcriptional activity of NFAT by promoting the nucleus translocation. Similarly, in LCWE-induced mice model, the expression of NFAT1 and NFAT2 and associated proinflammatory factors were increased significantly. In addition, by knocking down or overexpressing NFAT1 or NFAT2 in macrophages, the results indicated that NFAT signaling pathway mediated LCWE-induced immune responses in macrophages and regulated the synthesis of IL(interleukin)-6, IL-1β and TNF(tumor necrosis factor)-α in LCWE-induced macrophage activation. As well, we found that this process could be suppressed by CaN inhibitor CsA(cyclosporinA).

Conclusions: Therefore, the CaN/NFAT signaling pathway mediated LCWE-induced immune responses in macrophages, and also participated in the LCWE-induced CALs(coronary artery lesions). And also the inhibitory effect of CsA in LCWE-induced cell model towards a strategy to modulate the CaN/NFAT pathway during the acute course of KD might be helpful in alleviate KD-induced CALs.

Keywords: Activated T cell nuclear factor; Calcineurin inhibitor; Immune coronary artery injury; Kawasaki disease; Macrophage.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Extracts / adverse effects
  • Cell Wall / metabolism
  • Cell Wall / pathology
  • Genome-Wide Association Study
  • Interleukin-6 / metabolism
  • Lacticaseibacillus casei*
  • Macrophages / metabolism
  • Mice
  • Mucocutaneous Lymph Node Syndrome* / genetics
  • NFATC Transcription Factors / metabolism
  • Signal Transduction
  • Tumor Necrosis Factor-alpha / metabolism
  • Vasculitis* / complications
  • Vasculitis* / metabolism

Substances

  • Cell Extracts
  • Interleukin-6
  • Tumor Necrosis Factor-alpha
  • NFATC Transcription Factors