TLR5 activation induces secretory interleukin-1 receptor antagonist (sIL-1Ra) and reduces inflammasome-associated tissue damage
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Toll-like receptor-5 (TLR5)-mediated detection of flagellin induces nuclear factor (NF)-κB-mediated transcription of host defense gene expression, whereas recognition of intracellular flagellin by interleukin (IL)-1-converting enzyme protease-activation factor (IPAF) results in maturation/secretion of the inflammasome cytokine IL-1β. The potent effects of IL-1β are counter-regulated by secretory IL-1 receptor antagonist (sIL-1Ra). We studied the roles of flagellin receptors in regulating the expression of IL-1β and sIL-1Ra and their subsequent roles in inflammation. Flagellin induced sIL-1Ra in intestinal epithelia and macrophages in a dose- and time-dependent manner, whereas IL-1β was only induced in macrophages. In vivo, flagellin-induced sIL-1Ra, but not IL-1β, was absolutely dependent upon TLR5 expressed on non-hemopioetic cells. Thus, loss of TLR5 increased the IL-1β/sIL-1Ra ratio on flagellin treatment, which correlated with increased inflammatory pathology in response to this product. Furthermore, the flagellin/TLR5 interaction was important for the induction of sIL-1Ra and limiting inflammatory pathology on Salmonella infection. Finally, reduced sIL-1Ra levels in TLR5KO mice correlated with spontaneous colitis. Taken together, we demonstrate that intestinal epithelia, despite not expressing IL-1β, secrete sIL-1Ra in a TLR5-dependent manner suggesting that loss of TLR5 may promote inflammation by increasing IL-1β activity. Thus, optimizing the balance between inflammasome cytokines and their endogenous inhibitors might prove a useful strategy to treat inflammatory disorders.
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TLR5-/- mice developed spontaneous colitis due to increased bacterial burdens and reduced anti-inflammatory cytokine secretion.
“Further, TLR5–/– mice developed spontaneous colitis due to increased bacterial burdens and reduced anti-inflammatory cytokine secretion.166,170”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [170]
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- Authors
- Carvalho, F. A., Aitken, J. D., Gewirtz, A. T., & Vijay-Kumar, M.
- Affiliations
- Emory University (US)
- Venue
- Mucosal Immunology
- Publisher
- Elsevier BV
- Published
- 2011-01
- Volume
- 4
- Issue
- 1
- Pages
- 102-111
- ISSN
- 1933-0219 (ISSN-L)
- PMC
- PMC3012739
- OpenAlex
- W1993697908
- Cited by
- 80
- References
- 44
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 4 · 2023: 5 · 2022: 7 · 2021: 5 · 2020: 6 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 6 · 2015: 3 · 2014: 5 · 2013: 10 · 2012: 13
- FWCI
- 3.58
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Mucosal Immunology (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- HAL (submittedVersion)
- Funders
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (R24DK064399, R01DK061417, DK-061417, DK 064399, R01DK083890, K01DK083275)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Life Sciences › Immunology and Microbiology › Immunology › Inflammation biomarkers and pathways
- Keywords
- TLR5, flagellin, IL-1β, inflammasome, interstitial pneumonia with autoimmune features, NF-κB, intestinal epithelium, macrophages, salmonellosis, spontaneous colitis, inflammation
- MeSH terms
- Animals, Cell Line, Colitis, Enzyme-Linked Immunosorbent Assay, Flagellin, Gene Expression Regulation, Inflammation, Intestinal Mucosa, Macrophages, Mice, Inbred C57BL, RNA, Messenger, Salmonella Infections, Gene Expression, NF-kappa B, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Caspase 1, Toll-Like Receptor 5, Mice, Interleukin-1beta, Interleukin 1 Receptor Antagonist Protein, Inflammasomes
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