Synovial landscape unravels immune-stromal networks linking inflammation to fibrosis in osteoarthritis.
LAOUTEOUET D. 1, BORTOLOTTI O. 1, HANNEMANN N. 1, CHAMBON M. 1, MICHAUD H. 2, GLASSON Y. 2, DELIMA J. 3, LE GOFF B. 3, BLANCHARD F. 3, APPARAILLY F. 1, COURTIES G. 1
1 Institute for Regenerative Medicine & Biotherapies (IRMB), INSERM, University Hospital of Montpellier, University of Montpellier, Montpellier, France; 2 Montpellier Cancer Research Institute (IRCM), INSERM, University Hospital of Montpellier, University of Montpellier, Montpellier, France; 3 UMR 1238, Phy-OS, Bone Sarcoma and Remodeling of Calcified Tissues, INSERM, School of Medicine, University of Nantes, Nantes, France
Synovial macrophages are the most abundant immune cell type residing in healthy synovial tissue. Osteoarthritis (OA) is the most common form of degenerative joint disease characterized by progressive cartilage degradation, bone remodeling, and synovial inflammation resulting in joint dysfunction and loss of mobility. Here, we investigated the macrophage diversity in mice with OA, the respective contribution of macrophages according to their origin, as well as their putative interplay with other components of the synovial niche. Single-cell RNA sequencing was performed on knee synovial cells isolated from mice with collagenase-induced osteoarthritis (CiOA) versus PBS-treated animals (CTL). Eleven distinct clusters of cells were identified, including three defined as macrophages. The first macrophage cluster highly expressed genes associated with residency (Lyve1, Timd4, Trem2 and Folr2), the second cluster lacked these genes but expressed high levels of MHC-II-related genes (H2-Ab1, H2-Eb1 and CD74). The third macrophage cluster was enriched for inflammatory genes (Spp1, Mmp19, Il1b and Arg1). Additionally, a single-cell RNA sequencing was conducted on macrophages isolated from healthy and OA human synovial tissue, and a strong similarity in the gene signatures of macrophage clusters was observed in both species. Flow cytometry and immunofluorescence staining showed a significant recruitment of Tim4- monocyte-derived macrophages in OA concomitant to a massive rearrangement of synovial cells. Cell-cell communication analyses identified a privileged interaction between macrophages and stromal cells suggesting a dynamic interplay that participate to synovial fibrosis and inflammation in OA.