AB0097 ROLE OF TLR-4 AND IT’S DOWNREGULATORY PATHWAY IN ACUTE GOUTY ARTHRITIS
Authors: D. Bhadu, A. Choudhary, R. P. Goswami, U. Kumar
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> It has been proven that IL-1 is the key inflammatory cytokine in acute gout attack. There are three proposed pathways for the IL-1 activation and one important pathway is via TLR-4 and it's down regulatory signal molecules. Liu-Bryan et al [1] found that TLR knockout mice have decreased neutrophil influx in response to urate crystals while study by Chen et al [2] found no effect on neutrophils recruitment. Therefore, role of TLRs in urate signaling is still an open question. <h3>Objectives:</h3> To study the <b>TLR4</b> and its endogenous TLR4 ligands <b>(MRP8/14</b>) with down regulatory signal molecules myeloid differentiation primary response protein 88 (<b>MyD88</b>) in <b>IL-1</b> stimulation in acute gouty arthritis. <h3>Methods:</h3> The study included ten consecutive crystal proven gout of age &gt;18 years and seven primary OA patients (control subjects) attending the outpatient department. Patients with gout associated with other inflammatory arthritis or treated with steroids/colchicine were excluded. Synovial fluid and serum samples were centrifuged at 2500 rpm to isolate the supernatant from cells, and aliquots were stored at -80ºC. Quantitative tests were performed for biomarkers using commercial ELISA kits, TLR4, MRP8/14 MyD88, caspase-1 and IL-1 beta. <h3>Results:</h3> Clinical characteristics: all ten gout patients were male with a mean age of 37 years, while the control group (primary OA) had a female-to-male ratio of 4:3, with a mean age of 56 years. In synovial fluid, biomarkers like TLR4, MyD88, MRP8/14, Caspase-1 and IL-1ß were found to be positive in 100%, 90%, 100%, 100% &amp;90% of gout patients respectively, as opposed to 0% in all control subjects. The p-value was significant in synovial fluid for all the biomarkers. Serum levels were found positive in 100%, 90%,90%,100% % 20% for gout vs 0% in all control subjects. The p-value was significant for all biomarkers in serum except IL-1ß (p=0.485). The correlation analysis among different biomarkers shows overall low levels of correlation. However, IL1 levels were better correlated with MyD88 and had no correlation with Caspase1. Wilcoxon test for MyD88 vs Caspase-1 showed significant difference (z=-2.8, p&lt;0.05), suggesting that MyD88 dependent pathway plays a major role in activating IL-1. <h3>Conclusion:</h3> TLR-4 and it's downregulatory pathway has definite role in activating IL-1 causing acute gout attacks. Both MyD88 and inflammasome (caspase-1) dependent pathways are important for IL-1 activation. To the best of our knowledge, this study is the first to confirms the role of TLR4 and intracellular signaling pathway in human samples. To summarize, this study confirms the TLR4 and associated signaling pathway in the pathogenesis of gout, shedding light on potential future therapeutic targets. <h3>REFERENCES:</h3> [1] Liu-Bryan R, et al. <i>Arthritis Rheum</i> 52(9):2936–2946, 2005. [2] Chen CJ, et al. J Clin Invest 2006;116:2262–71. <h3>Acknowledgements:</h3> I acknowledge Dr Rojaleen Das for helping in sample storage. <h3>Disclosure of Interests:</h3> <b>None declared.</b>