Association of serum CCL20 levels with pulmonary vascular involvement and primary biliary cholangitis in patients with systemic sclerosis

Abstract

Aim: Systemic sclerosis (SSc) is a chronic autoimmune disease resulting in vasculopathy and fibrosis of the skin and major internal organs. Especially, interstitial lung disease and pulmonary arterial hypertension are the leading causes of mortality. C-C motif ligand 20 (CCL20) is known as a homeostatic and inflammatory chemokine, which is associated with fibrosis and angiogenesis and constantly expressed in organs involved in SSc. Therefore, we investigated the potential contribution of CCL20 to the development of SSc. Method:We conducted cross-sectional analyses of 67 SSc patients and 20 healthy controls recruited in a single center for 9 years. Serum CCL20 levels were measured by enzyme-linked immunosorbent assay. Statistical analyses were performed with the Mann-Whitney U test, the Kruskal-Wallis test followed by Dunn's multiple comparison test, Fisher's exact probability test and the Spearman's rank correlation coefficient.Results: SSc patients had significantly higher serum CCL20 levels than healthy controls. In SSc patients, serum CCL20 levels correlated inversely with the percentage of predicated diffusion lung capacity for carbon monoxide and positively with mean pulmonary artery pressure (mPAP). In addition, SSc patients with increased serum CCL20 levels had anti-mitochondrial antibody M2 titer significantly elevated relative to those with normal levels, and SSc patients with asymptomatic primary biliary cholangitis (PBC) possessed higher serum CCL20 levels than those without. Importantly, serum CCL20 levels were associated positively with mPAP values and PBC presence by multivariate regression analysis. Conclusion:Serum CCL20 levels may be involved in the development of pulmonary vascular involvement leading to pulmonary arterial hypertension and asymptomatic PBC in SSc patients.

Endothelial CCR6 expression due to FLI1 deficiency contributes to vasculopathy associated with systemic sclerosis

“…On the other hand, FLI1 deficiency is also implicated in the development of pulmonary arterial hypertension (PAH) by modulating the expression of angiogenesis-related genes [ 28 ]. Taken together with our recent data regarding the association of the CCL20/CCR6 axis with SSc-PAH [ 6 ], we hypothesized that FLI1 deficiency regulates the CCL20/CCR6 axis in the context of SSc vasculopathy.…”

“…This study was undertaken to investigate the role of the CCL20/CCR6 axis in the development of SSc vasculopathy because serum CCL20 levels correlate with mPAP values in SSc patients [ 6 ]. Given that mPAP is positively correlated with the severity of nailfold capillary changes [ 42 ], it was postulated that the activation of the CCL20/CCR6 axis plays a part in the destabilization of dermal small vessels.…”

“…Chemokines have attracted much attention as a potential therapeutic target family of molecules in the field of SSc based on the results of clinical studies and animal models [ 5 ]. With respect to CCL20, we have recently found that serum CCL20 levels correlate with mean pulmonary arterial pressure (mPAP) in SSc patients [ 6 ], suggesting that the CCL20/CCR6 axis underlies the developmental mechanism of SSc vasculopathy. According to previous studies, the CCL20/CCR6 axis promotes the chemotaxis of immature dendritic cells, T helper (Th) 17 cells, regulatory T cells, and B cells under both homeostatic and inflammatory conditions [ 7 ], contributing to the maintenance of homeostatic immune balance and the development of pathologic inflammation, such as psoriasis [ 8 , 9 ], atopic dermatitis [ 9 ], inflammatory bowel disease [ 10 ], systemic lupus erythematosus [ 11 ], dermatomyositis/polymyositis [ 12 ], and SSc [ 13 ].…”

Aberrant messenger RNA expression in peripheral blood mononuclear cells is associated with gouty arthritis

“…These factors, which are highly expressed during AGA pathogenesis, and have a strong chemotactic effect on certain immune cells. Chemokines are substances that attract immune cells to sites of biological activity, where they affect many BPs such as cell growth, angiogenesis, inflammation, and autoimmunity 31 …”

“…Chemokines are substances that attract immune cells to sites of biological activity, where they affect many BPs such as cell growth, angiogenesis, inflammation, and autoimmunity. 31 CXCL1 is a member of the CXC chemokine subfamily that acts as a chemotactic agent for a variety of immune cells, especially chemotactic neutrophils or other non-hematopoietic cells, to recruit the cells to a site of injury or infection and plays an important role in regulating immune and inflammatory reactions. In the periphery, CXCL1…”