Interleukin-37 Regulates Innate Immune Signaling in Human and Mouse Colonic Organoids
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, 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 supressing inflammatory signaling.
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Posted 17 Dec, 2020
On 05 Jan, 2021
Received 20 Dec, 2020
Received 20 Dec, 2020
Received 20 Dec, 2020
Received 20 Dec, 2020
Received 20 Dec, 2020
On 16 Dec, 2020
On 16 Dec, 2020
On 16 Dec, 2020
On 16 Dec, 2020
On 16 Dec, 2020
On 16 Dec, 2020
On 16 Dec, 2020
On 16 Dec, 2020
Invitations sent on 16 Dec, 2020
On 16 Dec, 2020
On 16 Dec, 2020
On 16 Dec, 2020
On 11 Dec, 2020
Interleukin-37 Regulates Innate Immune Signaling in Human and Mouse Colonic Organoids
Posted 17 Dec, 2020
On 05 Jan, 2021
Received 20 Dec, 2020
Received 20 Dec, 2020
Received 20 Dec, 2020
Received 20 Dec, 2020
Received 20 Dec, 2020
On 16 Dec, 2020
On 16 Dec, 2020
On 16 Dec, 2020
On 16 Dec, 2020
On 16 Dec, 2020
On 16 Dec, 2020
On 16 Dec, 2020
On 16 Dec, 2020
Invitations sent on 16 Dec, 2020
On 16 Dec, 2020
On 16 Dec, 2020
On 16 Dec, 2020
On 11 Dec, 2020
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, 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 supressing inflammatory signaling.
Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Due to technical limitations, full-text HTML conversion of this manuscript could not be completed. However, the manuscript can be downloaded and accessed as a PDF.