S100A9 aggravates bleomycin-induced dermal fibrosis in mice via activation of ERK1/2 MAPK and NF-κB pathways

Document Type: Original Article

Authors

1 Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu, China

2 Division of Rheumatology, Huashan Hospital, Fudan University, Shanghai 200040, China

3 State Key Laboratory of Genetic Engineering and Ministry of Education Key Laboratory of Contemporary Anthropology, School of Life Sciences, Fudan University, Shanghai 200433, China

Abstract

Objective(s): This study aims to investigate the pathogenicity and possible mechanisms of S100A9 function in mice models of scleroderma.
Materials and Methods: The content of S100A9 in the skin tissues of mice with scleroderma was determined. Different concentrations of bleomycin (BLM) and S100A9 were subcutaneously injected into the backs of mice simultaneously, and then pathological changes in the skin of these mice were monitored. Specifically, the levels of inflammatory cytokines and alpha smooth muscle actin (α-SMA), the activation of extracellular regulated kinase 1/2 (ERK1/2), mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) pathways, and the expression of the receptor for advanced glycation end-product (RAGE) in the skin were determined.
Results: The content of S100A9 in the skin tissues of mice with scleroderma was determined. Different concentrations of BLM and S100A9 were subcutaneously injected into the backs of mice simultaneously, and then pathological changes in the skin of these mice were monitored. Specifically, the levels of inflammatory cytokines and alpha smooth muscle actin (α-SMA), the activation of extracellular regulated kinase 1/2 (ERK1/2) mitogen-activated protein kinase (MAPK) and nuclear factor-kappa B (NF-κB) pathways, and the expression of the receptor for advanced glycation end-product (RAGE) in the skin were determined.
Conclusion: S100A9 aggravates dermal fibrosis in BLM-induced scleroderma (BIS ) mice, and its mechanisms might be mediated by RAGE, ERK1/2, and NF-κB pathway.

Keywords

Main Subjects


1.Varga J, Abraham D. Systemic sclerosis: a prototypic multisystem fibrotic disorder. J Clinical Invest 2007;117:557-567.

2.Yanaba K. Strategy for treatment of fibrosis in systemic sclerosis: Present and future. J Dermatol 2016;43:46-55.

3.Foell D, Wittkowski H, Vogl T, Roth J. S100 proteins expressed in phagocytes: a novel group of damage-associated molecularpattern molecules. J LeukocBiol 2007;81:28-37.

4.Ryckman C, Gilbert C, de Médicis R, Lussier A, Vandal K, Tessier PA. Monosodium urate monohydrate crystals induce the release of the proinflammatory protein S100A8/A9 from neutrophils. J LeukocBiol 2004;76:433-440.

5.Simard JC, Girard D, Tessier PA. Induction of neutrophil degranulation by S100A9 via a MAPK-dependent mechanism. J LeukocBiol 2010;87:905-914.

6.Schnekenburger J, Schick V, Krüger B, Manitz MP, Sorg C, Nacken W, et al. The calcium binding protein Sl00A9 is essential for pancreatic leukocyte infiltration and induces disruption of cell-cell contacts. J Cell Physiol 2008;216:558-567.

7.Kurzinski K, Torok KS. Cytokine profiles in localized scleroderma and relationship to clinical features. Cytokine 2011;55:157-164.

8.Tan FK, Zhou X, Mayes MD, Gourh P, Guo X, Marcum C,   et al. Signatures of differentially regulated interferon gene expression and vasculotrophism in the peripheral blood cells of systemic sclerosis patients. Rheumatology (Oxford) 2006;45:694-702.

9.Giusti L, Bazzichi L, Baldini C, Ciregia F, Mascia G, Giannaccini G, et al. Specific proteins identified in whole saliva from patients with diffuse systemic sclerosis. J Rheumatol 2007;34:2063-2069.

10.Fietta A, Bardoni A, Salvini R, Passadore I, Morosini M, Cavagna L, et al. Analysis of bronchoalveolar lavage fluid proteome from systemic sclerosis patients with or without functional, clinical and radiological signs of lung fibrosis. Arthritis Res Ther 2006;8:R160.

11.van Bon L, Cossu M, Loof A, Gohar F, Wittkowski H, Vonk M, et al. Proteomic analysis of plasma identifies the Toll-like receptor agonists S100A8/A9 as a novel possible marker for systemic sclerosis phenotype. Ann Rheum Dis 2014;73:1585-1589.

12.Xu X, Wu WY, Tu WZ, Chu HY, Zhu XX, Liang MR, et al. Increased expression of S100A8 and S100A9 in patients with diffuse cutaneous systemic sclerosis. A correlation with organ involvement and immunological abnormalities. Clin Rheumatol 2013;32:1501-1510.

13.Yamamoto T, Nishioka K. Cellular and molecular mechanisms of bleomycin-induced murine scleroderma: current update and future perspective. ExpDermatol 2005;14:81-95.

14.Foell D, Roth J. Proinflammatory S100 proteins in arthritis and autoimmune disease. Arthritis Rheum 2004;50:3762-3771.

15.Kumar RK, Harrison CA, Cornish CJ, Kocher M, Geczy CL. Immunodetection of the murine chemotactic protein CP-10 in bleomycin-induced pulmonary injury. Pathology 1998;30:51-56.

16.Kerkhoff C, Klempt M, Sorg C. Novel insights into structure and function of MRP8 (S100A8) and MRP14 (S100A9). BiochimBiophysActa 1998;1448:200-211.

17.Yamamoto T, Kuroda M, Nishioka K. Animal model of sclerotic skin. III: Histopathological comparison of bleomycin-induced scleroderma in various mice strains. Arch Dermatol Res 2000;292:535-541.

18.Nikitorowicz-Buniak J, Shiwen X, Denton CP, Abraham D, Stratton R. Abnormally differentiating keratinocytes in the epidermis of systemic sclerosis patients show enhancedsecretion of CCN2 and S100A9. J Invest Dermatol 2014;134:2693-2702.

19.Xu X, Chen H, Zhu X, Ma Y, Liu Q, Xue Y, et al. S100A9 promotes human lung fibroblast cells activation through receptor for advanced glycation end-product-mediated extracellular-regulated kinase 1/2, mitogen-activated protein-kinase and nuclear factor-κB-dependent pathways. ClinExpImmunol 2013;173:523-535.

20.Fullard N, O'Reilly S. Role of innate immune system in systemic sclerosis. SeminImmunopathol 2015;37:511-517.

21.Wu M, Mohan C. B-cells in systemic sclerosis: emerging evidence from genetics to phenotypes. CurrOpinRheumatol 2015;27:537-541.

22.Murdaca G, Spanò F, Contatore M, Guastalla A, Puppo F. Potential use of TNF-α inhibitors in systemic sclerosis. Immunotherapy 2014;6:283-289.

23.Neeper M, Schmidt AM, Brett J, Yan SD, Wang F, Pan YC, et al. Cloning and expression of a cell surface receptor for advanced glycosylation end products of proteins. J BiolChem 1992;267:14998-15004.

24.Heizmann CW, Ackermann GE, Galichet A. Pathologies involving the S100 proteins and RAGE. SubcellBiochem 2007;45:93-138.

25.Leclerc E, Vetter SW. The role of S100 proteins and their receptor RAGE in pancreatic cancer. BiochimBiophysActa 2015;1852:2706-2711.

26.He M, Kubo H, Ishizawa K, Hegab AE, Yamamoto Y, Yamamoto H, et al. The role of the receptor for advanced glycation end-products in lung fibrosis. Am J Physiol Lung Cell MolPhysiol 2007;293:L1427-1436.

27.Queisser MA, Kouri FM, Königshoff M, Wygrecka M, Schubert U, Eickelberg O, et al. Loss of RAGE in pulmonary fibrosis: molecular relations to functional changes in pulmonary cell types. Am J Respir Cell MolBiol 2008;39:337-345.

28.Yan L, Mathew L, Chellan B, Gardner B, Earley J, Puri TS,  et al. S100/Calgranulin-mediated inflammation accelerates left ventricular hypertrophy and aortic valvesclerosis in chronic kidney disease in a receptor for advanced glycation end products-dependent manner. ArteriosclerThrombVascBiol 2014;34:1399-1411.