Synovial macrophage diversity and activation of M-CSF signaling in post-traumatic osteoarthritis.

Autor:	Knights AJ; Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA., Farrell EC; Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA., Ellis OM; Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA., Song MJ; Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA., Appleton CT; Department of Physiology and Pharmacology, Western University, London ON, Canada.; Bone and Joint Institute, Western University, London, ON, Canada.; Department of Medicine, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada., Maerz T; Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.; Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA.; Department of Internal Medicine - Division of Rheumatology, University of Michigan, Ann Arbor, MI, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Oct 05. Date of Electronic Publication: 2023 Oct 05.
DOI:	10.1101/2023.10.03.559514
Abstrakt:	Objective: Synovium is home to immune and stromal cell types that orchestrate inflammation following a joint injury; in particular, macrophages are central protagonists in this process. We sought to define the cellular and temporal dynamics of the synovial immune niche in a mouse model of post-traumatic osteoarthritis (PTOA), and to identify stromal-immune crosstalk mechanisms that coordinate macrophage function and phenotype. Design: We induced PTOA in mice using a non-invasive tibial compression model of anterior cruciate ligament rupture (ACLR). Single cell RNA-seq and flow cytometry were used to assess immune cell populations in healthy (Sham) and injured (7d and 28d post-ACLR) synovium. Characterization of synovial macrophage polarization states was performed, alongside computational modeling of macrophage differentiation, as well as implicated transcriptional regulators and stromal-immune communication axes. Results: Immune cell types are broadly represented in healthy synovium, but experience drastic expansion and speciation in PTOA, most notably in the macrophage portion. We identified several polarization states of macrophages in synovium following joint injury, underpinned by distinct transcriptomic signatures, and regulated in part by stromal-derived macrophage colony-stimulating factor signaling. The transcription factors Pu.1, Cebpα, Cebpβ, and Jun were predicted to control differentiation of systemically derived monocytes into pro-inflammatory synovial macrophages. Conclusions: We defined different synovial macrophage subpopulations present in healthy and injured mouse synovium. Nuanced characterization of the distinct functions, origins, and disease kinetics of macrophage subtypes in PTOA will be critical for targeting these highly versatile cells for therapeutic purposes. Competing Interests: Competing interests The authors have no competing interests to declare.
Databáze:	MEDLINE
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