Ovariectomy Activates Chronic Low‐Grade Inflammation Mediated by Memory T Cells, Which Promotes Osteoporosis in Mice

Autor: Jessie Sanford, Elena Shashkova, Deborah J. Veis, Anna Cline-Smith, Macey Peterson, Linda Cox, Rajeev Aurora, Prabhjyot Panesar, Ángel Baldán, Mousumi Chakraborty, Ariel Axelbaum
Rok vydání: 2020
Předmět:
Zdroj: J Bone Miner Res
ISSN: 1523-4681
0884-0431
DOI: 10.1002/jbmr.3966
Popis: The loss of estrogen (E(2)) initiates a rapid phase of bone loss leading to osteoporosis in one-half of postmenopausal women, but the mechanism is not fully understood. Here, we show for the first time how loss of E(2) activates low-grade inflammation to promote the acute phase of bone catabolic activity in ovariectomized (OVX) mice. E(2) regulates the abundance of dendritic cells (DCs) that express IL-7 and IL-15 by inducing the Fas ligand (FasL) and apoptosis of the DC. In the absence of E(2), DCs become long-lived, leading to increased IL-7 and IL-15. We find that IL-7 and IL-15 together, but not alone, induced antigen-independent production of IL-17A and TNFα in a subset of memory T cells (T(MEM)). OVX of mice with T-cell–specific ablation of IL15RA showed no IL-17A and TNFα expression, and no increase in bone resorption or bone loss, confirming the role of IL-15 in activating the T(MEM) and the need for inflammation. Our results provide a new mechanism by which E(2) regulates the immune system, and how menopause leads to osteoporosis. The low-grade inflammation is likely to cause or contribute to other comorbidities observed postmenopause. © 2020 American Society for Bone and Mineral Research.
Databáze: OpenAIRE
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