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

Anna Cline-Smith, Ariel Axelbaum, Elena Shashkova, Mousumi Chakraborty, Jessie Sanford, Prabhjyot Panesar, Macey Peterson, Linda Cox, Angel Baldan, Deborah Veis, Rajeev Aurora

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

The loss of estrogen (E2) 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 E2 activates low-grade inflammation to promote the acute phase of bone catabolic activity in ovariectomized (OVX) mice. E2 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 E2, 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 (TMEM). 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 TMEM and the need for inflammation. Our results provide a new mechanism by which E2 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.

Original languageEnglish
Pages (from-to)1174-1187
Number of pages14
JournalJournal of Bone and Mineral Research
Volume35
Issue number6
DOIs
StatePublished - Jun 1 2020

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