Macrophage Dynamics During Bone Resorption and Chronic Inflammation

Abstract

Macrophages are located in all body tissues, contributing to tissue homeostasis by clearing foreign materials, dead cells, and debris. Macrophages are heterogeneous populations of immune cells that rapidly change their functions in response to local microenvironmental signals and also play various roles in both the induction and resolution of inflammation. In this review, we introduce our recent studies on the dynamics and functions of various cells of the macrophage lineage. We first focus on bone-resorbing macrophages (the osteoclasts). We recently found that S-adenosylmethionine-mediated DNA methylation catalysed by DNA methyltransferase 3a regulates osteoclastogenesis via epigenetic repression of antiosteoclastogenic genes. We also visualised the in vivo behavior of bone-resorbing macrophages in living bone using intravital two-photon microscopy, and found that sphingosine-1-phosphate, a lipid mediator, dynamically regulates both the migration and localisation of bone-resorbing macrophage precursor cells. Furthermore , we identified two distinct functional states of differentiated bone-resorbing macrophages, ('bone-resorptive [R]' and 'nonresorptive [N]'), and found that Th17 cells, a subset of CD4 + T cells, stimulated osteoclastic bone destruction by directly contacting N-state bone-resorbing macrophages to convert them to the R-state; this is a critical step in bone erosion within arthritic joints. Second, we discuss the roles played by adipose tissue macrophages during obesity-induced chronic inflammation. Using intravital imaging techniques, we have shown that the adipose tissue-expressed S100A8 gene plays a critical role in macrophage recruitment in the very early stages of obesity. This review provides new insights into the physiological and pathological roles of macrophages, and suggests potential novel therapies targeting aspects of macrophage dynamics in patients with chronic inflammatory diseases.