IL-34 contributes to the development of a pro-inflammatory microenvironmentin patients with Sjrogen's Syndrome

Abstract

Sjögrenʼs syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration of the exocrine glands. Keratoconjunctivitis sicca and xerostomia related to lachrymal and salivary gland, respectively, are the main clinical symptoms. Sjrogen syndrome can develop as a primary disorder affecting mainly the lacrimal and salivary gland or it can be secondary to other autoimmune disorders such us rheumatoid arthritis, sistemic lupus erythematosus or systemic sclerosis. (1). Diagnosis of the disease is dependent on the presence of antinuclear autoantibodies (especially Ro and La), hypergammaglobulinaemia, and rheumatoid factor. Recent evidence indicates, in the pathophysiology of SS, a major contribution of B cells, producing autoantibodies and several cytokines in the salivary glands. T lymphocytes are also involved in the local immune response in patients with pSS (2). Interleukin 34 is a recently described pro-inflammatory cytokine, expressed in numerous tissues that promote macrophage proliferation and differentiation and plays a central role in osteoclastogenesis. IL34 specifically binds to the CSF1 receptor promoting the phosphorylation of ERK1/2 and Akt (3). It has been recently demonstrated that IL34 is over-expressed in the synovial tissue of patients with rheumatoid arthritis promoting macrophage differentiation and contributing to the inflammation and bone erosion. Moreover IL34 promotes the growth and differentiation of CD14+ monocytes in PBMC (4). Many studies have underlined the crucial role of monocytes/macrophages in the expansion and organization of the inflammatory infiltrate in many autoimmune disorders such as Sjrogen syndrome (5). The objective of our study has been to investigate the expression of IL34 in labial salivary glands of patients with SS and its role in modulating a pro-inflammatory monocyte phenotype. Real-time PCR and immunohistochemical data show that IL34 is over-expressed both at m-RNA and protein levels in labial salivary glands of patients with SS; interleukin 34 expression is also correlated with the increased expression of IL1-β and TNF-α in SS patients compared to control and with the expansion of pro-inflammatory CD14(bright)CD16+ monocytes. Moreover in vitro stimulation of PBMC with IL34 induces a significant reduction of CD14(dim)CD16+ monocytes and the expansion of CD14(bright)CD16+. Our data suggest that IL34 can play a critical role in promoting the development of a pro-inflammatory monocyte phonotype in patients with Sjogren’s syndrome.