Journal
SCIENTIFIC REPORTS
Volume 11, Issue 1, Pages -Publisher
NATURE RESEARCH
DOI: 10.1038/s41598-021-87592-2
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Funding
- Canadian Institutes of Health Research (CIHR)
- Crohn's and Colitis Canada (CCC)
- Michael Smith Foundation for Health Research (MSFHR)
- Fonds de recherche du Quebec - Sante (FRQS)
- Four-Year Doctoral Fellowships from the University of British Columbia
- Natural Sciences and Engineering Research Council of Canada (NSERC)
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Studies have shown that intestinal epithelial cells exhibit inter-individual variability in innate immune responses to bacteria and host products, and IL-37 promotes IEC hypo-responsiveness by suppressing inflammatory signaling.
Intestinal epithelial cells (IEC) reside in close proximity to the gut microbiota and are hypo-responsive to bacterial products, likely to prevent maladaptive inflammatory responses. This is in part due to their strong expression of Single Ig IL-1 related receptor (SIGIRR), a negative regulator of interleukin (IL)-1 and toll-like receptor signaling. IL-37 is an anti-inflammatory cytokine that inhibits innate signaling in diverse cells by signaling through SIGIRR. Despite the strong expression of SIGIRR by IEC, few studies have examined whether IL-37 can suppress their innate immune signaling. We characterized innate immune responses of human and murine colonoids to bacteria (FliC, LPS) and host (IL-1 beta) products and the role of IL-37/SIGIRR in regulating these responses. We demonstrated that human colonoids responded only to FliC, but not to LPS or IL-1 beta. While colonoids derived from different donors displayed significant inter-individual variability in the magnitude of their innate responses to FliC stimulation, all colonoids released a variety of chemokines. Interestingly, IL-37 attenuated these responses through inhibition of p38 and NF kappa B signaling pathways. We determined that this suppression by IL-37 was SIGIRR dependent, in murine organoids. Along with species-specific differences in IEC innate responses, we show that IL-37 can promote IEC hypo-responsiveness by suppressing inflammatory signaling.
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