Increased expression of S100A8 and S100A9 in patients with diffuse cutaneous systemic sclerosis. A correlation with organ involvement and immunological abnormalities

Abstract

S100A8 and S100A9 play important roles in immune and inflammatory disorders. The role of the two proteins in systemic sclerosis (SSc) remains unknown. Fifty-seven diffuse cutaneous SSc (dcSSc) patients, 31 limited cutaneous SSc (lcSSc) patients were recruited in the present study. The expression of S100A8 and S100A9 in plasma was measured using an enzyme-linked immunosorbent assay and the mRNA levels in peripheral blood were assessed using reverse transcriptase quantitative PCR. The expression and distribution of S100A8, S100A9, and receptor for advanced glycation end products (RAGE), in skin tissues was analyzed by immunohistochemistry. The plasma concentrations of S100A8 and S100A9 were significantly higher in dcSSc patients than in normal controls and lcSSc patients. Both S100A8 and S100A9 levels were significantly increased in dcSSc patients with lung or kidney involvement. Increased plasma levels of S100A8 and S100A9 in dcSSc patients were associated with several autoantibodies. Transcription levels of S100A8 and S100A9 in peripheral blood were found elevated in both dcSSc and lcSSc patients than normal controls. Immunohistochemistry demonstrated higher S100A8 and S100A9 expression in sclerotic skin than in normal skin. The number of S100A8, S100A9, or RAGE positive fibroblasts was also significantly increased. Highly elevated expression of both S100A8 and S100A9 was found in dcSSc patients. There was close correlation with disease severity and serological abnormalities, suggesting that the two proteins may play important roles in the development of systemic sclerosis.

Proteomic analysis of plasma identifies the Toll-like receptor agonists S100A8/A9 as a novel possible marker for systemic sclerosis phenotype

“…The discrepancy between the correlation in patients with lcSSc versus dcSSc is however remarkable. Especially in the light of the recent publication showing S100A8/A9 being increased mainly in the dcSSc population, this might be explained due to differences between Asian and Caucasian populations or differences in inclusion criteria and/or technicalities of the ELISAs used 19. Earlier studies have shown an increase in SSc patient without making a subdivison 20 21.…”

Paquinimod reduces skin fibrosis in tight skin 1 mice, an experimental model of systemic sclerosis

“…Paquinimod binds to S100A9 and inhibits its binding to the pro-inflammatory receptors RAGE and TLR4 [15]. S100A9 may be directly involved in the fibrotic events occurring in SSc patients as S100A9 has been shown to stimulate proliferation and production of collagen by fibroblasts via binding to RAGE [19,27], but an indirect role where S100A9 affects innate immunity in the skin is however also possible. For example, mice lacking S100A9 have an impaired recruitment of myeloid cells to a wound, resulting in faster wound closure and less scar tissue formation [28].…”

“…The S100A9 protein has been identified as one target molecule for paquinimod [15]. S100A9 is involved in both activation and recruitment of myeloid cells into inflammatory sites [16] and a pro-inflammatory role for S100A9 is supported by elevated levels of S100A9 in several autoimmune/inflammatory diseases, including SSc [17][18][19]. Extracellular S100A9 acts as a damage-associated molecular pattern (DAMP) that interacts with a number of receptors, including toll-like receptor 4 (TLR4) and the receptor for advanced glycation end-product (RAGE) which are typical pattern recognition receptors expressed on cells within the myeloid compartment.…”

Biomarkers in connective tissue diseases

“…Their levels are higher in sera and bronchoalveolar lavage fluid from SSc patients. 101, 102 An independent study found increased levels in lcSSc patients with lung fibrosis and Scl70 positivity, but observed no correlation to pulmonary function tests. 103 Further studies are required to identify and validate specific biomarkers and their roles in pathogenesis, and to enable early prediction of patients who will need a lung transplant.…”