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Profibrotic Activation of Human Macrophages in Systemic Sclerosis
Author(s) -
Bhandari Rajan,
Ball Michael S.,
Martyanov Viktor,
Popovich Dillon,
Schaafsma Evelien,
Han Saemi,
ElTanbouly Mohamed,
Orzechowski Nicole M.,
Carns Mary,
Arroyo Esperanza,
Aren Kathleen,
Hinchcliff Monique,
Whitfield Michael L.,
Pioli Patricia A.
Publication year - 2020
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41243
Subject(s) - fibroblast , peripheral blood mononuclear cell , fibrosis , macrophage , monocyte , immunology , macrophage colony stimulating factor , microbiology and biotechnology , inflammation , chemistry , biology , medicine , in vitro , biochemistry
Objective Genome‐wide gene expression studies implicate macrophages as mediators of fibrosis in systemic sclerosis ( SS c), but little is known about how these cells contribute to fibrotic activation in SS c. We undertook this study to characterize the activation profile of SS c monocyte‐derived macrophages and assessed their interaction with SS c fibroblasts. Methods Plasma and peripheral blood mononuclear cells ( PBMC s) were obtained from whole blood from SS c patients (n = 24) and age‐ and sex‐matched healthy controls (n = 12). Monocytes were cultured with autologous or allogeneic plasma to differentiate cells into macrophages. For reciprocal activation studies, macrophages were cocultured with fibroblasts using Transwell plates. Results The gene expression signature associated with blood‐derived human SS c macrophages was enriched in SS c skin in an independent cohort and correlated with skin fibrosis. SS c macrophages expressed surface markers associated with activation and released CCL 2, interleukin‐6, and transforming growth factor β under basal conditions (n = 8) ( P < 0.05). Differentiation of healthy donor monocytes in plasma from SS c patients conferred the immunophenotype of SS c macrophages (n = 13) ( P < 0.05). Transwell experiments demonstrated that coculture of SS c macrophages with SS c fibroblasts induced fibroblast activation (n = 3) ( P < 0.05). Conclusion These data demonstrate that the activation profile of SS c macrophages is profibrotic. SS c macrophages are activated under basal conditions and release mediators and express surface markers associated with both alternative and inflammatory macrophage activation. These findings also suggest that activation of SS c macrophages arises from soluble factors in local microenvironments. These studies implicate macrophages as likely drivers of fibrosis in SS c and suggest that therapeutic targeting of these cells may be beneficial in ameliorating disease in SS c patients.