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CHOP-mediated IL-23 overexpression does not drive colitis in experimental spondyloarthritis

Fatemeh Navid1, Tejpal Gill2, Lilah Fones2

  • 1Pediatric Translational Research Branch, NIAMS, NIH, Bethesda, MD, 20892, USA. fatemeh.navid@nih.gov.

Scientific Reports
|May 29, 2024
PubMed

Insights

Deleting the transcription factor CHOP did not reduce gut inflammation in HLA-B27 transgenic rats. Instead, CHOP deficiency exacerbated inflammation, suggesting HLA-B27 does not cause gut disease via ER stress-induced IL-23.

Area of Science:

  • Immunology
  • Genetics
  • Gastroenterology

Background:

  • Human Leukocyte Antigen B27 (HLA-B27) is a significant risk factor for spondyloarthritis (SpA).
  • Endoplasmic reticulum (ER) stress and subsequent Interleukin-23 (IL-23) production are hypothesized mechanisms driving SpA pathogenesis.
  • HLA-B27 transgenic (Tg) rats exhibit SpA features, including gut inflammation.

Purpose of the Study:

  • To investigate the role of the transcription factor CHOP (a mediator of ER stress-induced IL-23) in gut inflammation in HLA-B27 Tg rats.
  • To determine if deleting CHOP affects IL-23 production and gut inflammation in this SpA model.

Main Methods:

  • Generated CHOP-deficient (Ddit3-/-) HLA-B27 Tg rats.
  • Assessed IL-23 production in macrophages and colonic immune cells.
  • Analyzed gene expression (transcriptome) and histological scores in the colon.
  • Utilized RNAScope to localize Il17a mRNA and CD3+ T cells in the colonic lamina propria.

Main Results:

  • CHOP deficiency abolished ER stress-mediated Il23a overexpression in macrophages and reduced Il23a expression in colonic immune cells.
  • Gut inflammation was not reduced; instead, pro-inflammatory gene expression (Il1a, Ifng, Tnf) and histological damage scores were increased in CHOP-deficient HLA-B27 Tg rats.
  • Il17a mRNA and CD3+ T cell localization remained similar in the presence and absence of CHOP.

Conclusions:

  • CHOP deficiency exacerbates, rather than ameliorates, gut inflammation in HLA-B27 Tg rats.
  • These findings indicate that HLA-B27 does not promote gut disease primarily through ER stress-induced IL-23.
  • CHOP may play a protective role against more severe HLA-B27-induced gut inflammation.

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