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The Role of Tumor Necrosis Factor Receptor 2 (TNFR2) in a Mouse Model of Valvular Inflammation and Fibrosis
Author(s) -
GonzálezTorres Mayra I.,
Meier Lee,
Auger Jennifer,
Binstadt Bryce
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1079.8
Subject(s) - fibrosis , inflammation , medicine , tumor necrosis factor alpha , extracellular matrix , pathology , h&e stain , immunology , immunohistochemistry , biology , microbiology and biotechnology
Fibrosis is increased production of extracellular matrix that results from chronic inflammation. Acquired cardiovascular diseases are the most significant source of morbidity and mortality worldwide and virtually all exhibit underlying fibrosis. The K/B.g7 mouse develops mitral valve (MV) inflammation and fibrosis with complete penetrance, spontaneous onset, and with many features that mirror human disease, and thus it provides a powerful tool for studying the effects of chronic inflammation on the cardiovascular system. We have found that fibrosis in this model is dominated by recruitment of circulating inflammatory monocytes rather than the local self‐renewal of resident macrophages that has been observed in other systems. Previous results lend support to a TNF/IL6‐VCAM1‐VLA4 axis mediating inflammatory cell recruitment and subsequent fibrogenesis in the K/B.g7 system. We next sought to determine the role for tumor necrosis factor receptor 1 (TNFR1) vs. TNFR2 in mediating endothelial activation in this pathway. Based on recent studies highlighting a role for TNFR2 in inflammatory monocyte recruitment, we hypothesized a similar role for TNFR2 in this system. We performed inhibition studies using anti‐TNFR2 monoclonal antibody injected biweekly beginning at the onset of valve disease. After 4 weeks of treatment, hearts were collected and frozen in liquid nitrogen. Coronal sections at 10 mm were stained with hematoxylin and eosin. MV thicknesses were measured using ImageJ and compared to IgG control treated animals. Histological analysis showed that TNFR2 inhibition did not reduce K/B.g7 mitral valve thickening and fibrosis. Rather, TNFR2 blockade resulted in a trend toward increased fibrosis and valve thickening. Due to TNFR2 expression in T regulatory cells (Treg), decreased Treg activity is one potential explanation for the trend toward increased fibrosis. Ongoing studies are investigating the roles of TNFR1 using bone marrow chimeras. These studies will enhance our understanding of cardiovascular fibrosis and could inform potential therapeutic strategies that target the inflammatory cell recruitment process in human fibrotic diseases.