Abstract
The interactions of fibroblast-like synoviocyte (FLS)-derived pro-inflammatory cytokines/chemokines and immune cells support the recruitment and activation of inflammatory cells in RA. Here, we show for the first time that the classical myokine myostatin (GDF-8) is involved in the recruitment of Th17 cells to inflammatory sites thereby regulating joint inflammation in a mouse model of TNFalpha-mediated chronic arthritis. Mechanistically, myostatin-deficiency leads to decreased levels of the chemokine CCL20 which is associated with less infiltration of Th17 cells into the inflamed joints. In vitro, myostatin alone or in combination with IL-17A enhances the secretion of CCL20 by FLS whereas myostatin-deficiency reduces CCL20 secretion, associated with an altered transmigration of Th17 cells. Thus, the communication between activated FLS and Th17 cells through myostatin and IL-17A may likely contribute to a vicious cycle of inflammation, accounting for the persistence of joint inflammation in chronic arthritis. Blockade of the CCL20–CCR6 axis by inhibition of myostatin may, therefore, be a promising treatment option for chronic inflammatory diseases such as arthritis.
Highlights
The interactions of fibroblast-like synoviocyte (FLS)-derived pro-inflammatory cytokines/chemokines and immune cells support the recruitment and activation of inflammatory cells in Rheumatoid arthritis (RA)
The aim of this study was to elucidate whether FLS-derived myostatin is involved in the recruitment of immune cells to the inflamed tissues and thereby contributes to the persistence of joint inflammation in a mouse model of TNFα-mediated chronic inflammation
Quantitative histomorphometric analysis showed considerably less joint inflammation by about 50% in hind paws and about 70% in knees of M stn−/− human TNFα transgenic (hTNFtg) compared to hTNFtg mice (Fig. 1a,b), substantiating an important regulatory role of myostatin in inflammation in arthritis
Summary
The interactions of fibroblast-like synoviocyte (FLS)-derived pro-inflammatory cytokines/chemokines and immune cells support the recruitment and activation of inflammatory cells in RA. The complex interaction of FLS-derived pro-inflammatory cytokines/chemokines and immune cells support the recruitment and activation of innate and adaptive inflammatory cells like T cells, B cells, neutrophils, monocytes/macrophages as well as dendritic cells, which migrate from the blood stream into the affected joints and contribute to RA progression[5,7,9,10,11,12,13]. We could further demonstrate that myostatin was significantly involved in inflammatory bone loss and its deletion or pharmacological inhibition diminished joint inflammation and destruction in various mouse models of arthritis[17] These data together with reduced inflammation upon blockade of myostatin in mice with chronic kidney disease (CKD)[18] point to a general role of myostatin in the regulation of chronic inflammation. The aim of this study was to elucidate whether FLS-derived myostatin is involved in the recruitment of immune cells to the inflamed tissues and thereby contributes to the persistence of joint inflammation in a mouse model of TNFα-mediated chronic inflammation
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