Journal ArticleDOI
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.
TLDR
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, which implicate innate immune cellular recognition of naked MSUstals by specific TLRs as a major factor in determining the inflammatory potential of MSU crystal deposits and the course of gouty arthritis.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.read more
Citations
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Journal ArticleDOI
Gout-associated uric acid crystals activate the NALP3 inflammasome
TL;DR: It is shown that MSU and CPPD engage the caspase-1-activating NALP3 (also called cryopyrin) inflammasome, resulting in the production of active interleukin (IL)-1β and IL-18 in mice deficient in the IL-1β receptor.
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Sterile inflammation: sensing and reacting to damage
Grace Y. Chen,Gabriel Núñez +1 more
TL;DR: The triggers and receptor pathways that result in sterile inflammation and its impact on human health are reviewed.
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How dying cells alert the immune system to danger
Hajime Kono,Kenneth L. Rock +1 more
TL;DR: Current knowledge of cell death and repair processes in the host and their importance to host defence and disease pathogenesis has only been appreciated relatively recently is reviewed.
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Toll-like receptors and cancer.
TL;DR: How the function of TLRs may relate to these processes in the context of carcinogenesis is discussed.
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The Inflammatory Response to Cell Death
Kenneth L. Rock,Hajime Kono +1 more
TL;DR: What is presently known about the sterile inflammatory response and its underlying mechanisms is reviewed.
References
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Cutting edge: Toll-like receptor 4 (TLR4)-deficient mice are hyporesponsive to lipopolysaccharide: evidence for TLR4 as the Lps gene product.
Katsuaki Hoshino,Osamu Takeuchi,Taro Kawai,Hideki Sanjo,Tomohiko Ogawa,Yoshifumi Takeda,Kiyoshi Takeda,Shizuo Akira +7 more
TL;DR: It is demonstrated that TLR4 is the gene product that regulates LPS response, and a single point mutation of the amino acid that is highly conserved among the IL-1/Toll receptor family is found.
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Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components.
Osamu Takeuchi,Katsuaki Hoshino,Taro Kawai,Hideki Sanjo,Haruhiko Takada,Tomohiko Ogawa,Kiyoshi Takeda,Shizuo Akira +7 more
TL;DR: It is demonstrated that TLR2 and TLR4 recognize different bacterial cell wall components in vivo andTLR2 plays a major role in Gram-positive bacterial recognition.
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Targeted Disruption of the MyD88 Gene Results in Loss of IL-1- and IL-18-Mediated Function
Osamu Adachi,Taro Kawai,Kiyoshi Takeda,Makoto Matsumoto,Hiroko Tsutsui,Masafumi Sakagami,Kenji Nakanishi,Shizuo Akira +7 more
TL;DR: It is demonstrated that MyD88 is a critical component in the signaling cascade that is mediated by IL-1 receptor as well as IL-18 receptor, and increases in interferon-gamma production and natural killer cell activity in response to IL- 18 are abrogated.
Journal ArticleDOI
Collaborative Induction of Inflammatory Responses by Dectin-1 and Toll-like Receptor 2
TL;DR: This report examines how dectin-1, a lectin family receptor for β-glucans, collaborates with TLRs in recognizing microbes and demonstrates that collaborative recognition of distinct microbial components by different classes of innate immune receptors is crucial in orchestrating inflammatory responses.