Oncostatin M deficiency leads to thymic hypoplasia, accumulation of apoptotic thymocytes and glomerulonephritis

Abstract

Oncostatin M (OSM) has been implicated in immune regulation, though its precise role remains elusive. Here we show that OSM plays a crucial role in the prevention of autoimmune diseases. OSM-deficient mice showed normal development of T cells, B cells and DC; however, their thymus showed hypoplasia and altered medullary structure. Autoantibodies against dsDNA accumulated and glomerulonephritis developed in aged OSMdeficient mice. Apoptotic cells accumulated in the thymus of OSM-deficient mice, and the administration of dexamethasone in young OSM-deficient mice resulted in the massive accumulation of apoptotic thymocytes and production of autoantibodies. These results suggest that OSM plays a key role in the prevention of autoimmune disease by regulating the clearance of apoptotic thymocytes.Key words: Apoptosis . Autoimmunity . Phagocytosis Supporting Information available online IntroductionOncostatin M (OSM) is a member of the IL-6 family of cytokines, and the OSM receptor (OSMR) consists of gp130 and the OSMRb subunit [1]. OSM is produced by a variety of cells including hematopoietic cells and fibroblasts, and is involved in various biological systems [2]. We showed previously that the lack of OSM signaling causes altered bone marrow microenvironment [3,4]. As OSM is also produced by Th1 cells and DC [5][6][7][8], OSM is suggested to play a role in immune reactions. In fact, OSM from activated DC regulates CCL21 expression in microvascular endothelial cells and promotes the trafficking of DC to LN [8].Moreover, Tg mice that express OSM using the lck proximal promoter exhibit thymic hypertrophy [9,10], suggesting that OSM may play a role in T-cell development within the thymic environment.Apoptosis is an essential process for development and homeostasis and defective clearance of apoptotic cells can lead to production of autoantibody by releasing cell debris, breaking peripheral tolerance. Macrophages in various tissues play an essential role in the elimination of apoptotic cells by phagocytosis. A vast majority of thymocytes are depleted by apoptosis during T-cell selections; however, apoptotic cells are barely detected in the thymus, indicating the presence of a mechanism to eliminate apoptotic thymocytes. Dying cells are normally removed rapidly from tissues by phagocytes, without eliciting inflammatory or immune responses. Clearance of apoptotic cells is crucial for prevention of autoimmune diseases [11,12] 1664with impaired macrophage phagocytosis exhibit splenomegaly due to accumulation of massive quantities of apoptotic cells and such defect in humans leads to retinitis pigmentosa [13].Previously, we demonstrated that OSM induces the development of thymic macrophages with strong phagocytic activity from intrathymic progenitors via OSM-responsive thymic epithelial cells (TEC) [14,15]. In this report, we show that OSM deficiency resulted in thymic hypoplasia, defective clearance of apoptotic thymocytes, accumulation of autoantibody and glomerulonephritis. Administration of dexamethasone (Dex) in OSM-defi...

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Therapeutic strategies for the clinical blockade of IL-6/gp130 signaling

“…Other gp130-related cytokines may, however, govern defined aspects of pathology, as is illustrated by the role of IL-11 and OSM in bone turnover (42). Indeed, OSMRβ-KO mice exhibit impaired hepatocyte proliferation (43) and altered monocytic cell trafficking (44), while OSM deficiency is associated with thymic hyperplasia and glomerulonephritis (45). Despite these apparent roles for other gp130-related cytokines in autoimmunity, therapies that target IL-6 or its receptor remain the most developed strategies.…”

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“…Mice deficient for OSM (OSM-KO) and OSM receptor β chain (OSMRβ-KO) were previously described [43,44] and obtained from Pr. A. Miyajima…”

“…Mice deficient for OSM (OSM-KO) and OSM receptor β chain (OSMRβ-KO) were previously described [43,44] and obtained from Pr. A. Miyajima (Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Japan).…”