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Research Article
Interleukin-37 Regulates Innate Immune Signaling in Human and Mouse Colonic Organoids
Bruce Vallance
British Columbia Children's Hospital
Corresponding Author
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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.
Keywords
IEC, SIGIRR, interleukin
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CURRENT STATUS: Under Review
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Posted 17 Dec, 2020
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On 05 Jan, 2021
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Reviewer #1 agreed
On 16 Dec, 2020
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On 16 Dec, 2020
Reviewer #3 agreed
On 16 Dec, 2020
Reviewer #2 agreed
On 16 Dec, 2020
Reviewer #6 agreed
On 16 Dec, 2020
Reviewer #7 agreed
On 16 Dec, 2020
Reviewer #5 agreed
On 16 Dec, 2020
Reviewer #8 agreed
On 16 Dec, 2020
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This preprint is under consideration at Scientific Reports. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Learn more about In Review
Research Article
Interleukin-37 Regulates Innate Immune Signaling in Human and Mouse Colonic Organoids
Bruce Vallance
British Columbia Children's Hospital
Corresponding Author
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 17 Dec, 2020
No community comments so far
Editorial decision: Major revision
On 05 Jan, 2021
Review #1 received
Received 20 Dec, 2020
Review #3 received
Received 20 Dec, 2020
Review #4 received
Received 20 Dec, 2020
Review #2 received
Received 20 Dec, 2020
Review #5 received
Received 20 Dec, 2020
Reviewer #1 agreed
On 16 Dec, 2020
Reviewer #4 agreed
On 16 Dec, 2020
Reviewer #3 agreed
On 16 Dec, 2020
Reviewer #2 agreed
On 16 Dec, 2020
Reviewer #6 agreed
On 16 Dec, 2020
Reviewer #7 agreed
On 16 Dec, 2020
Reviewer #5 agreed
On 16 Dec, 2020
Reviewer #8 agreed
On 16 Dec, 2020
Reviewers invited
Invitations sent on 16 Dec, 2020
Editor assigned
On 16 Dec, 2020
Editor invited
On 16 Dec, 2020
Submission checks complete
On 16 Dec, 2020
First submitted
On 11 Dec, 2020
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
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.