CXCL13 produced by macrophages due to Fli1 deficiency may contribute to the development of tissue fibrosis, vasculopathy and immune activation in systemic sclerosis

Abstract

CXCL13, a chemokine for B cells, follicular T cells, T helper 17 cells, and regulatory T cells, is reported to contribute to the development of systemic sclerosis (SSc), reflecting aberrant activation of immune system. To better understand the role of CXCL13 in SSc, we investigated the influence of Fli1 deficiency, a potential predisposing factor of this disease, on CXCL13 expression and assessed the clinical correlation of serum CXCL13 levels by multivariate regression analysis. Haploinsufficient loss of Fli1 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. 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. In particular, serum CXCL13 levels were associated with ILD and digital ulcers by multivariate regression analysis. Taken together, these results indicate that CXCL13 expression is upregulated by Fli1 deficiency in macrophages, potentially contributing to the development of tissue fibrosis, vasculopathy and immune activation in SSc, especially ILD and digital ulcers.

Possible association of decreased serum CXCL14 levels with digital ulcers in patients with systemic sclerosis

“…These results suggest that CXCL14 may be involved in the developmental process of DU in SSc, which seems to be sensitive to IVCY treatment. Given that CXCL14 serves as a chemoattractant for activated macrophages, immature dendritic cells and natural killer cells as well as an antiangiogenic factor, and that CXCL14 plays a role in fine‐tuning the strength of CXCL12‐mediated signal transduction, CXCL14 likely contributes to the pathogenesis of collagen diseases in a disease‐specific manner, as is the case with other CXCL chemokines …”

“…Given that CXCL14 serves as a chemoattractant for activated macrophages, immature dendritic cells and natural killer cells as well as an antiangiogenic factor, and that CXCL14 plays a role in fine-tuning the strength of CXCL12-mediated signal transduction, CXCL14 likely contributes to the pathogenesis of collagen diseases in a diseasespecific manner, as is the case with other CXCL chemokines. [33][34][35] SSc vasculopathy is characterized by the functional and structural abnormalities. The functional abnormalities include decreased endothelial function and the formation of microthrombi, which are attributable to the altered phenotype of endothelial cells.…”

“…On the other hand, it is generally accepted that dcSSc is characterized by Th2/Th17-skewed immune polarization, especially in its active phase, 41,42 and that IL-4, IL-13 and IL-17A, which are representative cytokines produced by Th2 and Th17 cells, are involved in the development of SSc-associated tissue fibrosis. [43][44][45] Given that various types of cells, such as dermal fibroblasts, endothelial cells, keratinocytes and macrophages, coordinately generate the microenvironment preferentially promoting Th2/Th17-skewed immune polarization in fibrotic organs of SSc, 35,[46][47][48][49] it is plausible that serum CXCL14 levels are decreased in SSc patients, especially in dcSSc patients.…”

Differential contribution of bone marrow-derived infiltrating monocytes and resident macrophages to persistent lung inflammation in chronic air pollution exposure

“…In our study the upregulation of TGF-β along with CXCL13 in TR-AΦ with 32-weeks of PM 2.5 exposure provides a possible mechanistic pathway of increased fibrosis. CXCL13, a chemokine that controls the trafficking of B cells has been recently demonstrated to be directly linked to pulmonary fibrosis 40,41 was also upregulated in PM 2.5 group at 4-weeks, and further increased by two-fold in TR-AΦ at 32-weeks. Using a four-way analysis of the transcriptomic data (Fig.…”

A focus on rare and undiagnosed skin diseases

“…The current collection of papers rounds off a series of closely related rare diseases/genodermatosis articles that have recently been published in the journal (see, for example, Kárpáti et al, Zingkou et al, Saigusa et al, Taniguchi et al and Boehner et al) documenting that these rare and often undiagnosed, but no less clinically important skin diseases offer fascinating new insights into basic biological principles, for which these dermatoses can serve as natural human models. Uncovering these principles carries the highest likelihood that more effective clinical management strategies can be offered to affected patients in the future.…”