ePoster Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Bisphosphonate drugs that target the skeleton also inhibit the mevalonate pathway in alveolar macrophages and boost immune responses to endotoxin in the lung. (#185)

Emma K Fletcher 1 2 , Oliver P Skinner 1 2 , Julie Jurczyluk 1 2 , Mark P Hodson 3 , Esther Kristianto 3 , Ya Xiao 1 4 , Philip M Hansbro 5 6 , Michael J Rogers 1 2 , Marcia A Munoz 1 2
  1. The Garvan Institute of Medical Research, Sydney, New South Wales, Australia
  2. St Vincent's Clinical School, UNSW Sydney, Sydney, New South Wales, Australia
  3. Victor Chang Cardiac Research Institute Innovation Centre, Sydney, New South Wales, Australia
  4. The Garvan Institute of Medical Research, Sydney, NSW, Australia
  5. Centre for Inflammation, Centenary Institute , Sydney, New South Wales, Australia
  6. University of Technology Sydney, Sydney, New South Wales, Australia

Nitrogen-containing bisphosphonates (N-BPs) are front-line treatments for preventing bone loss in patients with osteoporosis and metastatic bone disease. N-BPs are generally considered to act only in the skeleton due to their high affinity for calcium ions in bone mineral. These drugs exert anti-resorptive actions by disabling bone-degrading osteoclasts via inhibition of the mevalonate pathway. Surprisingly however, recent studies suggest that N-BPs also have beneficial, pleiotropic effects outside the skeleton, including a lower risk of pneumonia infection/mortality, but the mechanisms remain unknown. Like osteoclasts, macrophages in culture and in tumours in vivo efficiently internalise N-BPs by endocytosis. Thus, we sought to investigate whether BPs could also act directly on macrophages in the lung in vivo and potentially alter immune function.

We used fluorescently-labelled N-BP and flow cytometry to detect drug uptake into cells. 24 hours after iv injection, we detected N-BP in >98% of CD11blo/-CD11chiF4/80+ alveolar macrophages in lung, as well as 80% of peritoneal cells (almost entirely CD11b+F4/80+ large peritoneal macrophages). Characteristic features of N-BP action – inhibition of protein prenylation and build-up of the metabolite isopentenyl pyrophosphate – were also detected in alveolar and peritoneal macrophages 48 hours after one iv dose of the N-BP zoledronate. Importantly, systemic zoledronate treatment significantly enhanced the production of proinflammatory cytokines and chemokines in lung by 2.5-5-fold (including IL-1beta, IL-6, TNFalpha, CXCL1, CCL2,3,4,5) upon intranasal endotoxin challenge.

In summary, we present new evidence that N-BP treatment targets tissue resident macrophages in vivo in lung and peritoneum and enhances immune responses, dispelling the long-held dogma that these drugs act only in bone. Given that inhibition of the mevalonate pathway is known to have a variety of anti-microbial effects, we propose that the apparent beneficial effects of N-BP therapy on pneumonia infection and mortality occur by boosting the immune response of alveolar macrophages to infection.