Scientific Reports (2021-04-01)

Interleukin-37 regulates innate immune signaling in human and mouse colonic organoids

  • Joannie M. Allaire,
  • Anita Poon,
  • Shauna M. Crowley,
  • Xiao Han,
  • Zohreh Sharafian,
  • Navjit Moore,
  • Martin Stahl,
  • Brian Bressler,
  • Pascal M. Lavoie,
  • Kevan Jacobson,
  • Xiaoxia Li,
  • Bruce A. Vallance

Journal volume & issue
Vol. 11, no. 1
pp. 1 – 14


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Abstract 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-1β) 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-1β. 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 NFκB 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.