Innate immunity conferred by toll‐like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal–induced inflammation
Abstract
Objective: In gout, incompletely defined molecular factors alter recognition of dormant articular and bursal monosodium urate monohydrate (MSU) crystal deposits, thereby inducing self‐limiting bouts of characteristically severe neutrophilic inflammation. To define primary determinants of cellular recognition, uptake, and inflammatory responses to MSU crystals, we conducted a study to test the role of Toll‐like receptor 2 (TLR‐2), TLR‐4, and the cytosolic TLR adapter protein myeloid differentiation factor 88 (MyD88), which are centrally involved in innate immune recognition of microbial pathogens. Methods: We isolated bone marrow–derived macrophages (BMDMs) in TLR‐2 −/− , TLR‐4 −/− , MyD88 −/− , and congenic wild‐type mice, and assessed phagocytosis and cytokine expression in response to endotoxin‐free MSU crystals under serum‐free conditions. MSU crystals also were injected into mouse synovium‐like subcutaneous air pouches. Results: TLR‐2 −/− , TLR‐4 −/− , and MyD88 −/− BMDMs demonstrated impaired uptake of MSU crystals in vitro. MSU crystal–induced production of interleukin‐1β (IL‐1β), tumor necrosis factor α, keratinocyte‐derived cytokine/growth‐related oncogene α, and transforming growth factor β1 also were significantly suppressed in TLR‐2 −/− and TLR‐4 −/− BMDMs and were blunted in MyD88 −/− BMDMs in vitro. Neutrophil influx and local induction of IL‐1β in subcutaneous air pouches were suppressed 6 hours after injection of MSU crystals in TLR‐2 −/− and TLR‐4 −/− mice and were attenuated in MyD88 −/− mice. Conclusion: The murine host requires TLR‐2, TLR‐4, and MyD88 for macrophage activation and development of full‐blown neutrophilic, air pouch inflammation in response to MSU crystals. Our findings implicate innate immune cellular recognition of naked MSU crystals by specific TLRs as a major factor in determining the inflammatory potential of MSU crystal deposits and the course of gouty arthritis.
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Several purified endogenous molecules, including HSPs, HMGB1 and uric acid, can induce the production of pro-inflammatory cytokines through TLR2 and/or TLR4 in vitro.
“Although several of the purified endogenous molecules, including HSPs, HMGb1 and uric acid, can induce the production of pro-inflammatory cytokines through TLR2 and/or TLR4 in vitro25–27, the relevance of these observations has previously been questioned because of the possibility of microbial contamination: several of these proteins, including HSPs and HMGb1, bind lipopolysaccharide (LPS), making”
From Sterile inflammation: sensing and reacting to damage (2010) · cites this paper as [27]
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- Authors
- Liu‐Bryan, R., Scott, P., Sydlaske, A., Rose, D. M., & Terkeltaub, R.
- Affiliations
- University of California San Diego (US)
- Venue
- Arthritis & Rheumatism
- Publisher
- Wiley
- Published
- 2005-09
- Volume
- 52
- Issue
- 9
- Pages
- 2936-2946
- ISSN
- 0004-3591 (ISSN-L)
- 1529-0131
- OpenAlex
- W2045895870
- Cited by
- 414
- References
- 56
- Citations by year
- 2026: 16 · 2025: 15 · 2024: 22 · 2023: 14 · 2022: 25 · 2021: 12 · 2020: 21 · 2019: 19 · 2018: 17 · 2017: 13 · 2016: 18 · 2015: 20 · 2014: 27 · 2013: 20 · 2012: 18
- FWCI
- 11.97
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Arthritis & Rheumatism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r03ar049416-03)
- National Heart, Lung, and Blood Institute (HL077360, R01HL077360)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR049416, P30-AR-43360)
- Topics
- Health Sciences › Medicine › Nephrology › Gout, Hyperuricemia, Uric Acid
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- gout, monosodium urate crystals, TLR2, TLR4, MyD88, innate immunity, macrophage phagocytosis, crystal-induced inflammation, neutrophil recruitment, IL-1β, air pouch inflammation
- MeSH terms
- Animals, Antigens, Differentiation, Bone Marrow Cells, Disease Models, Animal, Immunity, Innate, Macrophages, Mice, Inbred C57BL, Phagocytosis, Receptors, Immunologic, Specific Pathogen-Free Organisms, Uric Acid, Arthritis, Gouty, Cytokines, Mice, Knockout, Adaptor Proteins, Signal Transducing, Toll-Like Receptor 2, Toll-Like Receptor 4, Mice, Myeloid Differentiation Factor 88
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