title: Modulation of TNF-induced macrophage polarization by synovial fibroblasts.
abstract: Mesenchymal stromal cells have emerged as powerful modulators of the immune system. In this study, we explored how the human macrophage response to TNF is regulated by human synovial fibroblasts, the representative stromal cell type in the synovial lining of joints that become activated during inflammatory arthritis. We found that synovial fibroblasts strongly suppressed TNF-mediated induction of an IFN-β autocrine loop and downstream expression of IFN-stimulated genes (ISGs), including chemokines CXCL9 and CXCL10 that are characteristic of classical macrophage activation. TNF induced the production of soluble synovial fibroblast factors that suppressed the macrophage production of IFN-β, and cooperated with TNF to limit the responsiveness of macrophages to IFN-β by suppressing activation of Jak-STAT signaling. Genome-wide transcriptome analysis showed that cocultured synovial fibroblasts modulate the expression of approximately one third of TNF-regulated genes in macrophages, including genes in pathways important for macrophage survival and polarization toward an alternatively activated phenotype. Pathway analysis revealed that gene expression programs regulated by synovial fibroblasts in our coculture system were also regulated in rheumatoid arthritis synovial macrophages, suggesting that these fibroblast-mediated changes may contribute to rheumatoid arthritis pathogenesis. This work furthers our understanding of the interplay between innate immune and stromal cells during an inflammatory response, one that is particularly relevant to inflammatory arthritis. Our findings also identify modulation of macrophage phenotype as a new function for synovial fibroblasts that may prove to be a contributing factor in arthritis pathogenesis.
authors: Arthritis and Tissue Degeneration Program and the David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021; donlinl@hss.edu.
authors: Laura T
authors: LT
authors: Donlin
authors: Arthritis and Tissue Degeneration Program and the David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021;
authors: Arundathi
authors: A
authors: Jayatilleke
authors: Arthritis and Tissue Degeneration Program and the David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021; Biological Sciences Department, New York City College of Technology, City University of New York, New York, NY 11201;
authors: Eugenia G
authors: EG
authors: Giannopoulou
authors: Arthritis and Tissue Degeneration Program and the David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021; Department of Medicine, Weill Cornell Medical College, New York, NY 10021; and.
authors: George D
authors: GD
authors: Kalliolias
authors: Arthritis and Tissue Degeneration Program and the David Z. Rosensweig Genomics Research Center, Hospital for Special Surgery, New York, NY 10021; Department of Medicine, Weill Cornell Medical College, New York, NY 10021; and Weill Cornell Graduate School of Medical Sciences, New York, NY 10021.
authors: Lionel B
authors: LB
authors: Ivashkiv
mesh_terms: D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D019898:Autocrine Communication / Q000276:immunology; D002478:Cells, Cultured; D054357:Chemokine CXCL10 / Q000276:immunology; D054370:Chemokine CXCL9 / Q000276:immunology; D018920:Coculture Techniques; D005260:Female; D005347:Fibroblasts / Q000276:immunology* / Q000473:pathology; D055106:Genome-Wide Association Study; D006801:Humans; D016899:Interferon-beta / Q000276:immunology; D053612:Janus Kinases / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008297:Male; D050791:STAT Transcription Factors / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013583:Synovial Membrane / Q000276:immunology* / Q000473:pathology; D014158:Transcription, Genetic / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
chemical_list: C114753:CXCL10 protein, human; C080810:CXCL9 protein, human; D054357:Chemokine CXCL10; D054370:Chemokine CXCL9; D050791:STAT Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D016899:Interferon-beta; D053612:Janus Kinases