Fli1 deficiency promotes CXCL13 expression from macrophages, contributing to the development of systemic sclerosis

Takashi Taniguchi, Yoshihide Asano, Takashi Yamashita, Kouki Nakamura, Ryosuke Saigusa, Yohei Ichimura, Takehiro Takahashi, Tetsuo Toyama, Ayumi Yoshizaki, Shinichi Sato.

Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.

CXCL13, a chemokine for B cells, follicular T cells, T helper 17 cells, and regulatory T cells with an anti-angiogenic property, is reported to contribute to the development of systemic sclerosis (SSc). To better understand the role of CXCL13 in SSc, we initially looked at CXCL13 expression in Fli1-deficient fibroblasts, endothelial cells, and macrophages because Fli1 deficiency, a potential predisposing factor of SSc, induces SSc-like phenotypes in various types of cells. Of note, haploinsufficient loss of the Fli1 gene remarkably induced CXCL13 expression in murine peritoneal macrophages, while gene silencing of FLI1 did not affect the expression of CXCL13 in human dermal fibroblasts and human dermal microvascular endothelial cells. Further analyses with sera of SSc patients revealed that serum CXCL13 levels were elevated in SSc patients compared with healthy controls and correlated positively with skin score and negatively with pulmonary function test results. SSc patients with elevated serum CXCL13 levels had longer disease duration, diffuse cutaneous involvement, interstitial lung disease (ILD), heart involvement, pulmonary arterial hypertension, Raynaud’s phenomenon, pitting scars, digital ulcers, telangiectasia, and high serum IgG levels more frequently than the other patients. Importantly, serum CXCL13 levels were associated with ILD and digital ulcers by multivariate regression analysis. Given that macrophage-derived CXCL13 promotes the formation of germinal centers in lymphoid tissues and the infiltration of Th17 cells into the affected organs, and that CXCL13 inhibits angiogenesis by interfering with basic fibroblast growth factor, Fli1 deficiency-dependent up-regulation of CXCL13 in macrophages may contribute to the development of tissue fibrosis, vasculopathy, and immune activation in SSc, especially ILD and digital ulcers.