Hidekata Yasuoka1, Yuen Yu Angela Tam1, Yuka Okazaki1,2, Yuichi Tamura3, Koichi Matsuo4, Carol Feghali-Bostwick5, Tsutomu Takeuchi1, Masataka Kuwana1,2. 1. Division of Rheumatology, Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan. 2. Department of Allergy and Rheumatology, Graduate School of Medicine, Nippon Medical School, Tokyo, Japan. 3. International University of Health and Welfare, Mita Hospital, Tokyo, Japan. 4. Laboratory of Cell and Tissue Biology, School of Medicine, Keio University, Tokyo, Japan. 5. Medical University of South Carolina, Charleston, SC, USA.
Abstract
Objectives: To investigate the systemic sclerosis-related phenotype in fos-related antigen-1 transgenic mice and its underlying mechanisms. Methods: Lung and skin sections of constitutive fos-related antigen-1 transgenic mice and wild-type mice were examined by tissue staining and immunohistochemistry. The tricuspid regurgitation pressure gradient was measured by transthoracic echocardiography with a Doppler technique. To assess the impact of fos-related antigen-1 expression on macrophage function, bone marrow-derived mononuclear cells were derived from mice that expressed fos-related antigen-1 under the control of doxycycline and wild-type littermates. These bone marrow-derived mononuclear cells were induced to differentiate into macrophages with or without doxycycline, and analyzed for gene and protein expression. Finally, lung explants obtained from systemic sclerosis patients and control donors were subjected to immunohistochemistry. Results: The lungs of fos-related antigen-1 transgenic mice showed excessive fibrosis of the interstitium and thickening of vessel walls, with narrowing lumen, in an age-dependent manner. The tricuspid regurgitation pressure gradient was significantly elevated in fos-related antigen-1 transgenic versus control mice. Increased dermal thickness and the loss of subdermal adipose tissue were also observed in the fos-related antigen-1 transgenic mice. These changes were preceded by a perivascular infiltration of mononuclear cells, predominantly consisting of alternatively activated or M2 macrophages. Overexpressing fos-related antigen-1 in bone marrow-derived mononuclear cell cultures increased the expression of M2-related genes, such as Il10, Alox15, and Arg1. Finally, fos-related antigen-1-expressing M2 macrophages were increased in the lung tissues of systemic sclerosis patients. Conclusions: The fos-related antigen-1 transgenic mouse serves as a genetic model of systemic sclerosis that recapitulates the major vascular and fibrotic manifestations of the lungs and skin in systemic sclerosis patients. M2 polarization mediated by the up-regulation of fos-related antigen-1 may play a critical role in the development of systemic sclerosis.
Objectives: To investigate the systemic sclerosis-related phenotype in fos-related antigen-1 transgenic mice and its underlying mechanisms. Methods: Lung and skin sections of constitutive fos-related antigen-1 transgenic mice and wild-type mice were examined by tissue staining and immunohistochemistry. The tricuspid regurgitation pressure gradient was measured by transthoracic echocardiography with a Doppler technique. To assess the impact of fos-related antigen-1 expression on macrophage function, bone marrow-derived mononuclear cells were derived from mice that expressed fos-related antigen-1 under the control of doxycycline and wild-type littermates. These bone marrow-derived mononuclear cells were induced to differentiate into macrophages with or without doxycycline, and analyzed for gene and protein expression. Finally, lung explants obtained from systemic sclerosis patients and control donors were subjected to immunohistochemistry. Results: The lungs of fos-related antigen-1 transgenic mice showed excessive fibrosis of the interstitium and thickening of vessel walls, with narrowing lumen, in an age-dependent manner. The tricuspid regurgitation pressure gradient was significantly elevated in fos-related antigen-1 transgenic versus control mice. Increased dermal thickness and the loss of subdermal adipose tissue were also observed in the fos-related antigen-1 transgenic mice. These changes were preceded by a perivascular infiltration of mononuclear cells, predominantly consisting of alternatively activated or M2 macrophages. Overexpressing fos-related antigen-1 in bone marrow-derived mononuclear cell cultures increased the expression of M2-related genes, such as Il10, Alox15, and Arg1. Finally, fos-related antigen-1-expressing M2 macrophages were increased in the lung tissues of systemic sclerosis patients. Conclusions: The fos-related antigen-1 transgenic mouse serves as a genetic model of systemic sclerosis that recapitulates the major vascular and fibrotic manifestations of the lungs and skin in systemic sclerosis patients. M2 polarization mediated by the up-regulation of fos-related antigen-1 may play a critical role in the development of systemic sclerosis.
Authors: Paulius Venalis; Gábor Kumánovics; Hendrik Schulze-Koops; Alfiya Distler; Clara Dees; Pawel Zerr; Katrin Palumbo-Zerr; László Czirják; Zygmunt Mackevic; Ingrid E Lundberg; Oliver Distler; Georg Schett; Jörg H W Distler Journal: Arthritis Rheumatol Date: 2015-02 Impact factor: 10.995
Authors: Susan K Mathai; Mridu Gulati; Xueyan Peng; Thomas R Russell; Albert C Shaw; Ami N Rubinowitz; Lynne A Murray; Jonathan M Siner; Danielle E Antin-Ozerkis; Ruth R Montgomery; Ronald A S Reilkoff; Richard J Bucala; Erica L Herzog Journal: Lab Invest Date: 2010-04-19 Impact factor: 5.662
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