TY - JOUR TI - Bisphosphonate drugs have actions in the lung and inhibit the mevalonate pathway in alveolar macrophages AU - Munoz, Marcia A AU - Fletcher, Emma K AU - Skinner, Oliver P AU - Jurczyluk, Julie AU - Kristianto, Esther AU - Hodson, Mark P AU - Sun, Shuting AU - Ebetino, Frank H AU - Croucher, David R AU - Hansbro, Philip M AU - Center, Jacqueline R AU - Rogers, Michael J A2 - Shoback, Dolores A2 - Isales, Carlos A2 - Martin, T John A2 - Massaia, Massimo A2 - Plotkin, Lilian VL - 10 PY - 2021 DA - 2021/12/30 SP - e72430 C1 - eLife 2021;10:e72430 DO - 10.7554/eLife.72430 UR - https://doi.org/10.7554/eLife.72430 AB - Bisphosphonates drugs target the skeleton and are used globally for the treatment of common bone disorders. Nitrogen-containing bisphosphonates act by inhibiting the mevalonate pathway in bone-resorbing osteoclasts but, surprisingly, also appear to reduce the risk of death from pneumonia. We overturn the long-held belief that these drugs act only in the skeleton and show that a fluorescently labelled bisphosphonate is internalised by alveolar macrophages and large peritoneal macrophages in vivo. Furthermore, a single dose of a nitrogen-containing bisphosphonate (zoledronic acid) in mice was sufficient to inhibit the mevalonate pathway in tissue-resident macrophages, causing the build-up of a mevalonate metabolite and preventing protein prenylation. Importantly, one dose of bisphosphonate enhanced the immune response to bacterial endotoxin in the lung and increased the level of cytokines and chemokines in bronchoalveolar fluid. These studies suggest that bisphosphonates, as well as preventing bone loss, may boost immune responses to infection in the lung and provide a mechanistic basis to fully examine the potential of bisphosphonates to help combat respiratory infections that cause pneumonia. KW - osteoporosis KW - pneumonia KW - bisphosphonate KW - prenylation KW - alveolar macrophage KW - inflammasome JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -