An IL-23R/IL-22 Circuit Regulates Epithelial Serum Amyloid A to Promote Local Effector Th17 Responses
Open accessAbstract
RORγt(+) Th17 cells are important for mucosal defenses but also contribute to autoimmune disease. They accumulate in the intestine in response to microbiota and produce IL-17 cytokines. Segmented filamentous bacteria (SFB) are Th17-inducing commensals that potentiate autoimmunity in mice. RORγt(+) T cells were induced in mesenteric lymph nodes early after SFB colonization and distributed across different segments of the gastrointestinal tract. However, robust IL-17A production was restricted to the ileum, where SFB makes direct contact with the epithelium and induces serum amyloid A proteins 1 and 2 (SAA1/2), which promote local IL-17A expression in RORγt(+) T cells. We identified an SFB-dependent role of type 3 innate lymphoid cells (ILC3), which secreted IL-22 that induced epithelial SAA production in a Stat3-dependent manner. This highlights the critical role of tissue microenvironment in activating effector functions of committed Th17 cells, which may have important implications for how these cells contribute to inflammatory disease.
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Induction of intestinal Th17 cells by gut microbes has been suggested as the mechanism of microbiota-dependent exacerbation of EAE disease in multiple studies.
“Interestingly, the induction of intestinal Th17 cells by gut microbes has been suggested as the mechanism of microbiota-dependent exacerbation of EAE disease in multiple studies [50, 184, 185, 187].”
From TH17 cell heterogeneity and its role in tissue inflammation (2023) · cites this paper as [50]
In multiple autoimmune disease mouse models, including EAE, autoimmune arthritis, and autoimmune renal disease, microbiota-specific induction of intestinal Th17 cells is associated with worsened autoimmune disease at extra-intestinal sites.
“Indeed, in multiple autoimmune disease mouse models, including EAE, autoimmune arthritis, and autoimmune renal disease, the microbiota-specific induction of intestinal Th17 cells was found to be associated with worsened autoimmune disease at extra-intestinal sites [50–52].”
From TH17 cell heterogeneity and its role in tissue inflammation (2023) · cites this paper as [50]
IL-22 prompts epithelial cells to make SAA1 and SAA2 in a paracrine manner, which is needed to activate ileal TH17 cells.
“which subsequently induces the production of the proteins serum amyloid A1 and serum amyloid A2 from the epithelium in a paracrine fashion — a process that is required for the activation of TH17 cells in the ileum113.”
From Diet–microbiota interactions as moderators of human metabolism (2016) · cites this paper as [113]
In the ileum, IL-23 triggers innate lymphoid cells to release IL-22.
“IL-23 causes the release of IL-22 from innate lymphoid cells in the ileum”
From Diet–microbiota interactions as moderators of human metabolism (2016) · cites this paper as [113]
Physical interactions between SFB and enterocytes are required for induction of Th17-polarizing molecules SAA and IL-1β.
“Physical interactions between SFB and enterocytes, to which the bacteria are tightly anchored, are required for the induction of Th17-polarizing molecules (SAA, IL-1β) [33, 34].”
From Antibiotic-Induced Changes in the Intestinal Microbiota and Disease (2016) · cites this paper as [33]
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References 57 · Cited by 547
- Authors
- Sano, T., Huang, W., Hall, J. A., Yang, Y., Chen, A., Gavzy, S. J., Lee, J.-Y., Ziel, J. W., Miraldi, E. R., Domingos, A. I., Bonneau, R., & Littman, D. R.
- Affiliations
- New York University (US)
- Howard Hughes Medical Institute (US)
- Courant Institute of Mathematical Sciences (US)
- Instituto Gulbenkian de Ciência (PT)
- Corresponding author
- Littman, Dan R.
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2015-10
- Volume
- 163
- Issue
- 2
- Pages
- 381-393
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC4621768
- OpenAlex
- W2118455790
- Cited by
- 547
- References
- 57
- Citations by year
- 2026: 19 · 2025: 29 · 2024: 33 · 2023: 43 · 2022: 66 · 2021: 70 · 2020: 63 · 2019: 66 · 2018: 38 · 2017: 64 · 2016: 40 · 2015: 14
- FWCI
- 25.64
- Type
- journal article
- Language
- en
- Update notices
- erratum (2016-01-14)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Human Frontier Science Program
- Howard Hughes Medical Institute
- National Institutes of Health (R01DK103358, T32 CA009161_Levy)
- Cancer Research Institute
- Damon Runyon Cancer Research Foundation (2105-12)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Psoriasis: Treatment and Pathogenesis
- Life Sciences › Immunology and Microbiology › Immunology › IL-33, ST2, and ILC Pathways
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- Th17 cells, IL23R, IL-22, serum amyloid A, RORγt, segmented filamentous bacteria, ILC3, IL-17A, STAT3, intestinal epithelium, mucosal immunity, autoimmunity, gut microbiota, tissue microenvironment
- MeSH terms
- Gastrointestinal Microbiome, Interleukin-22, Serum Amyloid A Protein, Animals, Immunity, Innate, Interleukins, Intestines, Lymphocytes, Mice, Inbred C57BL, Signal Transduction, Receptors, Interleukin, Mice, Th17 Cells
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