Item request has been placed! ×
Item request cannot be made. ×
loading  Processing Request

Proteoglycan-4 is an Essential Regulator of Synovial Macrophage Polarization and Inflammatory Macrophage Joint Infiltration

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
اقرأ أكثر حفظ في قائمتي
  • معلومة اضافية
    • بيانات النشر:
      Research Square Platform LLC, 2021.
    • الموضوع:
      2021
    • نبذة مختصرة :
      Background: Synovial macrophages (SMs) perform a multitude of functions that include clearance of cell debris and foreign bodies, tissue immune surveillance, and resolution of inflammation. At one end of the macrophage polarization spectrum is the inflammatory phenotype (M1), which secretes IL-1β, IL-6 and expresses iNOS. On the opposite end of the spectrum is the anti-inflammatory phenotype (M2) which is characterized by the secretion of IL-10 and TGF-β. PRG4 is an important regulator of synovial hyperplasia and fibrotic remodeling and the involvement of SM activation in PRG4’s homeostatic role is yet to be defined. Our objectives were to study PRG4’s importance to SM homeostasis, M1 and M2 polarization and joint infiltration of bone marrow-derived macrophages (BMDMs) and investigate the role of SMs in mediating synovial fibrosis in Prg4 gene-trap (Prg4GT/GT) murine knee joints.Methods: SM phenotyping in Prg4GT/GT and Prg4+/+ joints was performed using flow cytometry and the balance between CD86+/CD206- (M1) and CD86-/CD206+ (M2) SMs was studied as animals aged. Expression of iNOS and IL-6 in CD86+ SMs, arginase-1 in CD206+ SMs and the impact of Prg4 recombination on SM polarization and BMDM infiltration following a TLR2 agonist challenge were determined. Inflammatory SMs were depleted using liposomal clodronate and synovial membrane thickness and expression of fibrotic markers: α-SMA, PLOD2 and collagen type I (COL-I) were assessed using immunohistochemistry.Results: Total macrophages in Prg4GT/GT joints were higher than corresponding age-matched Prg4+/+ joints (p) and the percentages of CD86+/CD206- and CD86+/CD206+ SMs increased in Prg4GT/GT joints as animals aged (p), whereas the percentage of CD86-/CD206+ SMs decreased (p). CD86+ SMs expressed iNOS and IL-6 compared to CD86- SMs (p) while CD206+ SMs also expressed arginase-1. Prg4 re-expression limited the accumulation of CD86+ SMs, increased CD86-/CD206+ SMs and attenuated BMDM recruitment (p). Liposomal clodronate reduced inflammatory SMs and in turn reduced synovial hyperplasia, α-SMA, PLOD2 and COL-I expression in the synovium (p).Conclusions: SM accumulation in the joint and the balance between inflammatory and anti-inflammatory SM subsets are regulated by PRG4. In the absence of PRG4’s role, the synovium is populated with inflammatory macrophages that drive synovial fibrosis.
    • File Description:
      application/pdf
    • ISSN:
      1478-6362
    • الرقم المعرف:
      10.21203/rs.3.rs-402481/v1
    • الرقم المعرف:
      10.1186/s13075-021-02621-9
    • Rights:
      CC BY
      URL: http://creativecommons.org/licenses/by/4.0/Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (http://creativecommons.org/licenses/by/4.0/) . The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ (http://creativecommons.org/publicdomain/zero/1.0/) ) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
    • الرقم المعرف:
      edsair.doi.dedup.....67aa4cbe529793f22523a237e8d1b410