Background/Purpose: Tissue-resident monocyte-lineage cell (TRMC) are an extravascular population distinct from circulating monocytes and synovial macrophages and are critical for the development of inflammatory arthritis. Previous fate-mapping results demonstrated that TRMC are at least partially derived from the fetal liver and are traceable using various myeloid-related fate-mapping models, suggesting potential heterogeneity within this population. However, the precise identities and origins of TRMC subpopulations remain unclear.

Methods: We first measured the long-lived and bone marrow (BM)-derived TRMC in bone marrow chimeras (BMC) and parabiosis mice. Next, we used single-cell RNA-sequencing with surface marker detection (CITE-seq) to investigate the heterogeneity of TRMC during homeostasis and their dynamic changes after the synovial disruption induced by clodronate-laden liposome (Clo. Lip) and throughout the progression of RA-like disease in mice. To investigate the dependence of TRMC subpopulations on Ccr2, we utilized BMC and parabiosis mice models between CD45.1 B6 and Ccr2-/- mice.

Results: We characterized the ontogeny of TRMC, which comprises both bone-marrow (BM)-derived and long-lived populations. Furthermore, CITE-seq identified three TRMC subpopulations, distinguished by TIM4, CX3CR1, and MHCII surface marker expression, each exhibiting distinct functions. TIM4+CX3CR1+ TRMC were enriched for pathways involved in synovial hemostasis, whereas MHCII+ TRMC were more enriched for inflammatory response pathways, with TIM4+ TRMC exhibiting functional features of both. Clo. Lip modestly reduced the absolute number of TRMC but did not impact proportions or transcriptional profile of TRMC at 7 days post administration. Under steady state, TIM4+CX3CR1+ and TIM4+ TRMC represented the long-lived population, whereas MHCII+ TRMC were BM-derived and dependent on Ccr2. During synovial inflammation, BM-derived TRMC expanded up to threefold at the peak of arthritis compared to baseline and replenished the TIM4+CX3CR1+ and TIM4+ TRMC compartments. Additionally, TIM4+ TRMC underwent transcriptional and functional changes resembling MHCII+ TRMC during the peak and plateau stages of RA-like arthritis in mice.

Conclusion: These findings underscore the heterogeneity within TRMC and highlight their distinct responses to synovial disruption and potential roles in rheumatoid arthritis (RA). Future therapeutic target strategies should focus on TRMC by targeting their specific subpopulations.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/ra-required-synovial-tissue-resident-monocyte-lineage-cells-are-comprised-of-three-distinct-subpopulations/