Synovial macrophages: from ordinary eaters to extraordinary multitaskers

Like other tissues, joints contain resident macrophages, and their diversity is only beginning to be characterized. Based on the highlights of recent studies, we discuss where current challenges lie propose new avenues for future research in osteoarticular field. In adult mammals, macrophages are found all tissues organs body. Tissue specialized phagocytes that have a variety supportive functions tissue development, homeostasis, immunity. They extremely heterogeneous terms origin, phenotype, functions, genetic program includes conserved core signature unique each niche [1.The Immunological Genome Consortium et al Gene-expression profiles transcriptional regulatory pathways underlie identity mouse macrophages.Nat. Immunol. 2012; 13: 1118-1128Crossref PubMed Scopus (1193) Google Scholar]. Recent reports revealed within human joint [2.Culemann S. al.Locally renewing synovial provide protective barrier joint.Nature. 2019; 572: 670-675Crossref (122) Scholar, 3.Alivernini al.Distinct macrophage subsets regulate inflammation remission rheumatoid arthritis.Nat. Med. 2020; 26: 1295-1306Crossref (55) 4.Zhang F. al.Defining inflammatory cell states arthritis by integrating single-cell transcriptomics mass cytometry.Nat. 20: 928-942Crossref (218) 5.Kuo D. al.HBEGF+ induce fibroblast invasiveness.Sci. Transl. 11eaau8587Crossref (42) Emerging evidence indicates tissue-resident neighbors constitute complex microenvironments known as niches [6.Guilliams M. al.Establishment maintenance niche.Immunity. 52: 434-451Abstract Full Text PDF (72) Similarly forest ecosystem, unit which its components sense interact with maintain homeostasis. Synovial can also viewed biological occupy defined place supports functions. The architecture bony vertebrate comprises environment bridges two articulating bones. divided into well-defined areas: (i) lining layer, formed fibroblasts build an epithelial-like flanking intra-articular fluid, bone, or cartilage, well ligaments tendons; (ii) sublining layer – loose connective fibroblasts, lymphatic vessels, small venules, macrophages. discoveries heterogeneity among cells general, particular, match this historical dual architecture. Indeed, studies identified distinct clusters specific areas membrane (Table 1), thus reinforcing idea layers truly not differ structure density but composition Scholar].Table 1Macrophage tissuesaThis classification based phenotypic markers [3–5] [3], cluster-defining genes, subanatomical locations, gene ontology (GO)-based putative respective abundance health disease. right column presents counterparts when available [2].Phenotypic marker [3.Alivernini Scholar]Subset Scholar]Cluster Scholar]Putative functions/signature(GO-based)AnatomicdistributionConditionOverlappingclustersMouse Scholar]MerTK+CD206+TREM2TIMD4PhagocytosisEfferocytosisHost defenseImmune regulationMatrix remodelingLiningnicheHealth remissionNUPR1 [4]C1QA [4.Zhang 2 [5.Kuo Scholar]CX3CR1TREM2FOLR2LYVE1RELM-?ICAMCytokines/chemokinesCX3CR1ID2Self-maintenanceMerTK?CD206?HLAISG15InterferonProinflammatorySubliningnicheActive arthritisIFN 4 Scholar]CCR2/ARG1CLEC10AAntigen presentationIL1B 1 Scholar]CCR2/IL1BCD48S100A12Leukocyte recruitmentProinflammatorySPP1Bone resorptionCluster Scholar]CCR2/ARG1a This Scholar] Scholar], Open table tab Over past few years elegant RNA sequencing (scRNA-seq) fate-mapping approaches existence several healthy Mouse shown exhibit uneven heterogeneity, single homogeneous population up four different Four similar were synovium highlighting features these species [7.Hannemann N. al.New insights arthritis.Joint Bone Spine. 2021; 88: 105091Crossref (2) 1). Beyond signatures, strategies mice including lineage-tracing parabiosis experiments combined flow cytometry proliferation assays immunofluorescence stainings suggest proliferating contribute renewal Although no contribution from circulating monocytes was evidenced experiments, earlier study using bone marrow transplantation showed subset replaced derived blood [8.Misharin A.V. al.Non-classical Ly6C? drive development mice.Cell Rep. 2014; 9: 591-604Abstract (152) scRNA-seq screens, ontogenic origins, developmental lineage relationships therefore remain explored. humans, ontology-based analyses indicate MerTK+ include homeostatic such efferocytosis, matrix remodeling, antimicrobial activities Another type rooted fibroblast. Fibroblasts source extracellular proteins collagens, fibronectin, hyaluronic acid, glycosaminoglycans scaffolding structuring maintaining ecosystem. they high degree according anatomic distribution Scholar,9.Croft A.P. damage arthritis.Nature. 570: 246-251Crossref (182) Scholar,10.Mizoguchi al.Functionally disease-associated Commun. 2018; 789Crossref (158) Overall, transcriptomic analyses, seem more diverse than those niche. context inflammation, ecosystem network change substantially. thin rapidly loses integrity, followed hyperplasia, area undergoes extensive remodeling concomitantly massive infiltration leukocyte invaders, lymphocytes. vitro stimulation isolated (RA) biopsies comparable production anti-inflammatory tissue-remodeling cytokines response lipopolysaccharide However, activated produce proinflammatory whereas release inflammation-resolving lipid mediator resolvin D1 restricted Several lines there dynamic interplay between environment. coculture RA patients indicated influence profiles. license repair responses increasing expression transforming growth factor ? collagen genes. By contrast, trigger emergence pro-destructive enriched genes encoding mediators interleukin (IL)-6, cartilage degradation erosion receptor activator nuclear ?B ligand (RANKL) metalloproteinases (MMPs) turn, set factors rewire towards responses, thereby leading activation enhanced recruitment immune As such, epidermal (EGF)–EGF (R) axis contributes dialog promotes invasiveness Matrigel invasion assay Scholar,11.Zhou X. al.Circuit design stable two-cell system.Cell. 172: 744-757Abstract (101) pioneering cellular sources cytokines, chemokines, factors, together signaling most niche-specific cell–cell circuits integrity discovered. paradigm established before birth self-maintain throughout mammalian adulthood. some organs, mixed marrow-derived pool [12.Ginhoux Guilliams Tissue-resident ontogeny homeostasis.Immunity. 2016; 44: 439-449Abstract (654) So far, considered embryonic although initial work suggests discrete might originate recently discovered questions origins both niches, particularly area. contrast counterparts, residence time monocyte-derived generally short. If acquired during adulthood, how do immigrants successfully adapt integrate community? Can completely overcome pool? How what extent permissive? Answering will crucial understanding occurs upon infection trauma, it affect, irreversibly not, span longevity joints. functional properties identified. Of note, lung interstitial harbor blood-derived populations reside close either nerve fibers vessels; been nonoverlapping contributing homeostasis [13.Chakarov al.Two coexist across subtissular niches.Science. 363eaau0964Crossref (203) Because highly innervated vascularized, topic investigation whether associated localizations. These challenge dualistic view 'bad guys' relative Given help us dig deeply gene-enriched relate quiescent paramount. need bear mind initially remarkable plasticity. One compare datasets murine multiple territories at steady-state, settings, amazed similarity clusters. list defines cluster, interesting epigenetic influences, networks, signals clusters; may allow better underlying mechanisms licensing addition 'omic' methods, investigating downstream protein level enable translation findings level. With multiplexed imaging cytometry, now examine unprecedented detail any microenvironment. technical advances mapped under physiological conditions various disorders, RA, ankylosis spondylarthritis, osteoarthritis. Side-by-side comparisons answers why subsequently inform clinical outcomes treatments. Ultimately, serve optimize biopsy-based precision personalized medical strategies. For lingering questions, immunological community needs further investigate contributions cell-intrinsic versus -extrinsic fate, plasticity subsets. sociological integration process, successful immigrant requires establishment multidirectional communication systems actors involved, starting neighbors. supported part INSERM, University Montpellier, French National Research Agency (ANR-18-CE14-0042-01), Society Rheumatology (SFR 4939). authors declare conflicts interest.