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CHOP-mediated IL-23 overexpression does not drive colitis in experimental spondyloarthritis
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CHOP-mediated IL-23 overexpression does not drive colitis in experimental spondyloarthritis
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Journal Article
CHOP-mediated IL-23 overexpression does not drive colitis in experimental spondyloarthritis
2024
Overview
HLA-B27 is a major risk factor for spondyloarthritis (SpA), yet the underlying mechanisms remain unclear. HLA-B27 misfolding-induced IL-23, which is mediated by endoplasmic reticulum (ER) stress has been hypothesized to drive SpA pathogenesis. Expression of HLA-B27 and human β
2
m (hβ
2
m) in rats (HLA-B27-Tg) recapitulates key SpA features including gut inflammation. Here we determined whether deleting the transcription factor CHOP (
Ddit3−
/−), which mediates ER-stress induced IL-23, affects gut inflammation in HLA-B27-Tg animals. ER stress-mediated
Il23a
overexpression was abolished in CHOP-deficient macrophages. Although CHOP-deficiency also reduced
Il23a
expression in immune cells isolated from the colon of B27+ rats,
Il17a
levels were not affected, and gut inflammation was not reduced. Rather, transcriptome analysis revealed increased expression of pro-inflammatory genes, including
Il1a
,
Ifng
and
Tnf
in HLA-B27-Tg colon tissue in the absence of CHOP, which was accompanied by higher histological Z-scores. RNAScope localized
Il17a
mRNA to the lamina propria of the HLA-B27-Tg rats and revealed similar co-localization with
Cd3e
(CD3) in the presence and absence of CHOP. This demonstrates that CHOP-deficiency does not improve, but rather exacerbates gut inflammation in HLA-B27-Tg rats, indicating that HLA-B27 is not promoting gut disease through ER stress-induced IL-23. Hence, CHOP may protect rats from more severe HLA-B27-induced gut inflammation.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ Animals
/ Colitis
/ Colitis - chemically induced
/ Colon
/ Endoplasmic Reticulum Stress
/ Histocompatibility antigen HLA
/ HLA-B27 Antigen - metabolism
/ Humanities and Social Sciences
/ Humans
/ Interleukin-23 Subunit p19 - genetics
/ Interleukin-23 Subunit p19 - metabolism
/ Rats
/ Science
/ Spondylarthritis - metabolism
/ Spondylarthritis - pathology
/ Transcription Factor CHOP - genetics
