Chemokines and chemokine receptors in the pathogenesis of systemic sclerosis

Abstract

Activation of the immune system and increased synthesis of extracellular matrix proteins by fibroblasts are hallmarks in the pathogenesis of systemic sclerosis (SSc). The mechanisms that initiate the accumulation of inflammatory cells are still unknown. Chemokines are a family of small molecules that are divided into subfamilies according to the position of NH2-terminal cysteine motif. A new nomenclature for chemokines recently has been introduced in an attempt to overcome the confusion resulting from a number of different names for the same chemokines. Recent data indicate that chemokines, and in particular MCP-1 (CCL2), might be involved in the pathogenesis of SSc at different levels. MCP-1 is highly upregulated in skin specimens from SSc patients compared with those from healthy controls. Dermal fibroblasts release MCP-1, which is able to induce and perpetuate the migration of inflammatory cells into the skin. Interestingly, data from animal models, as well as from in vitro studies, indicate that MCP-1 might also be involved in the increased synthesis of extracellular matrix proteins, by either direct or indirect mechanisms. In conclusion, chemokines represent interesting candidates for target-directed therapies for SSc. This concept has to be confirmed by further studies using animal models for SSc and other fibrotic diseases.

Biomarkers in Systemic Sclerosis: An Overview

“…Recent studies have shown how vast and ever-expanding the field of biomarkers is in SSc. Biomarkers will become increasingly important in research and, consequently, in the diagnosis and therapeutic approach to SSc [30][31][32][33][34][35][36][59][60][61][62][63][64][65][66][67]. Several studies have demonstrated the involvement of at least 240 pathways and numerous dysregulated proteins in the pathogenesis of SSc, so the field of biomarkers in this disease is complex and evolving [30][31][32][33][34][35][36][59][60][61][62][63][64][65][66][67].…”

“…Biomarkers will become increasingly important in research and, consequently, in the diagnosis and therapeutic approach to SSc [30][31][32][33][34][35][36][59][60][61][62][63][64][65][66][67]. Several studies have demonstrated the involvement of at least 240 pathways and numerous dysregulated proteins in the pathogenesis of SSc, so the field of biomarkers in this disease is complex and evolving [30][31][32][33][34][35][36][59][60][61][62][63][64][65][66][67]. Cytokeratin 17 (CK17), marginal zone protein B1 (MZB1), and leucine-rich α2-glycoprotein-1 (LRG1) appear to be potential biomarkers for SSc, with CK17 negatively associated with disease severity and higher values of CK17 protective [37,[59][60][61][62][63][64][65][66][67].…”

“…The most used biomarkers in SSc are autoantibodies, and in this case, they have utility for diagnosis, classification, and prognosis of the disease; it should also be mentioned that biomarkers can be potential therapeutic targets [4,[23][24][25][26][27][28][29][30]. Antinuclear antibodies (ANA) are present in more than 90% of SSc patients, along with anticentromere, anti-Th/To, and anti-topoisomerase I antibodies, which are considered the classic biomarkers present in 60% of SSc patients and help to define precise clinical classifications [4,7,[29][30][31][32][33][34][35][36][37]. Other autoantibodies, such as those directed against the endothelium or fibroblasts, against angiotensin II type 1 receptor, endothelin-1 type A receptor, platelet-derived growth factor receptor (anti-PDGFR), and extracellular matrix (ECM) proteins [16][17][18][19][20][38][39][40][41][42][43][44][45] are also found in SSc patients.…”

Target organ expression and biomarker characterization of chemokine CCL21 in systemic sclerosis associated pulmonary arterial hypertension

“…Given their critical role in immune cell function, it is hardly surprising that chemokines appear important for the development and propagation of autoimmune diseases; and may represent useful biomarkers for disease evolution. In SSc, it was early shown that the CC chemokine 2 (CCL2) was important for the development of tissue fibrosis (7). More recently, studies indicate biomarker potential of additional chemokines including CCL18, CX3CL1 and CXCL4 in SScassociated interstitial lung disease (5,(8)(9)(10).…”

Pathogenese der systemischen Sklerose (Sklerodermie)

“…Eine wichtige Rolle könnten dabei Chemokine spielen. Bei Chemokinen handelt es sich um eine Familie kleiner Proteine, welche die Migration von Leukozyten im Rahmen eines Entzündungsgeschehens steuern[51]. Etliche Chemokine weisen in der SSc ein abnormes Expressionsmuster auf.…”