Background/Purpose: Toll-like receptors (TLRs) play a pivotal role in innate immune system and chronic inflammation in autoimmune diseases. It has been reported that signaling pathways via TLRs, such as TLR2, TLR3, TRL4, TLR7 and TLR9 are involved in onset and/or development of primary Sjögren’s syndrome (pSS), and that immune cells expressing TLRs, such as macrophages, dendritic cells, monocytes and B cells play a crucial role in the pathogenesis of the disease. We reported that elevated expression of BAFF receptor, BR3, in peripheral monocytes in pSS patients is correlated with clinical parameters of the patients and is involved in abnormal B cell functions. Therefore, clarification of regulatory mechanisms of the BR3 expression in monocytes is required not only for elucidation of pathogenesis of pSS, but also for search for therapeutic targets of the disease. In this study, we investigated possible involvement of signaling through TLRs in the enhanced expression of BR3 in peripheral pSS monocytes.

Methods: The expression levels of CD14, CD16, BR3 and TLRs in peripheral monocytes from pSS patients (n = 67) and healthy controls (HC; n = 19) were analyzed by FACS.The mRNA levels of BR3 and TLR4 in the monocytes were analyzed by quantitative PCR (qPCR). The serum level of S100A9, one of the ligands for TLR4, was measured by ELISA. PBMCs were stimulated with LPS or S100A9 for 3 days and the expression level of BR3 in the cells was analyzed by FACS.

Results: FACS analysis revealed that the expression of TLR4 was significantly higher in CD14⁺⁺CD16⁺ cells (intermediate monocytes, IM) than that of CD14⁺⁺CD16^– (classical monocytes) and CD14⁺CD16⁺⁺ (non-classical monocytes) in pSS. Interestingly, not only the proportion of BR3-positive cells, but also that of TLR4-positive cells among IM was significantly higher in pSS than that of HC (p < 0.001 for BR3 and TLR4). The data is consistent with the results with qPCR. In addition, the proportion of TLR4-positive cells was significantly and positively correlated with that of BR3-positive cells only in pSS (p < 0.01). Notably, TLR4 ligands such as LPS or S100A9 enhanced the BR3 expression in peripheral monocytes. It may be noteworthy that the serum level of S100A9 was significantly higher in pSS than HC (p< 0.001) and the proportion of TLR-positive cells among IM was significantly correlated with the S100A9 level in pSS (P < 0.05).

Conclusion: Our results together with the data that the BR3 expression level is correlated with clinical parameters of pSS collectively suggest that TLR4 signaling pathways are involved in the pathogenesis of pSS.

« Back to ACR Convergence 2023

ACR Meeting Abstracts - https://acrabstracts.org/abstract/possible-involvement-of-tlr4-in-the-pathogenesis-of-primary-sjogrens-syndrome-through-induction-of-the-expression-of-baff-receptor-br3-in-peripheral-monocytes/