Cellular composition of tissue-resident monocyte-lineage cells reveals transcriptional heterogeneity during inflammatory arthritis.

Tissue-resident monocyte-lineage cells (TRMCs) are an extravascular population distinct from circulating monocytes and synovial macrophages and are critical for the development of inflammatory arthritis. However, the precise identities and origins of TRMC subpopulations remain unclear. Here, we characterize the ontogeny of TRMCs, which are comprised of bone marrow (BM)-derived and an embryonic, long-lived population. Furthermore, we identified 3 TRMC subpopulations, distinguished by expression of TIM4, CX3CR1, and MHCII. Clodronate-laden liposomes reduce the number of TRMCs but do not impact the proportions or transcriptional profiles of TRMC subpopulations at 7 d postadministration. TIM4+CX3CR1+ and TIM4+ TRMCs represent long-lived subpopulations, whereas MHCII+ TRMCs are BM-derived and dependent on Ccr2 during steady state. BM-derived TRMCs expand and replenish TIM4+CX3CR1+ and TIM4+ TRMC compartments throughout the peak and plateau of inflammatory arthritis. These findings underscore the importance of heterogeneity within TRMCs and highlight their distinct responses to synovial disruption and potential roles in rheumatoid arthritis.