Aging in an osteoimmunological context; the contribution of the macrophage.
- Author(s): Clark, Daniel Robert
- Advisor(s): Marcucio, Ralph
- et al.
Aging is characterized by physiologic changes leading to a predisposition to a myriad of age-related diseases. Accompanying these age-related diseases is a process of systemic inflammatory dysregulation known as inflamm-aging. This body of work focuses on fracture healing and periodontal disease, as both involve dysregulation of inflammation within bone and both demonstrate increased complications or prevalence with age. We chose to investigate the macrophage and its contribution to age-related pathologies affecting bone. Macrophages are important regulators of inflammation during fracture healing and periodontal disease. An improved understanding of the age-related changes to macrophages will advance our understanding of the biology of aging and lead to enhanced healthcare for the aging population.
Mouse models of fracture healing and periodontal disease using young and old mice were employed in this work. Macrophages from young and old mice were characterized via RNA-seq. Macrophage were depleted pharmacologically during disease or fracture healing to elucidate the contribution of macrophages within the given models.
The results demonstrated that macrophages from old mice present an aged-macrophage phenotype with increased pro-inflammatory and M1 gene expression. By eliminating the influence of the aged macrophage phenotype via macrophage depletion, periodontal disease severity was significantly reduced and fracture healing was significantly improved. Further, we have demonstrated that TREM2 expression on macrophages is decreased with age which drove increased inflammatory cytokine expression and poorer fracture healing outcomes. Taken together, the aged-related changes that occur to the macrophage are likely involved in numerous disease pathologies, and this work presents potential therapeutic targets to address the macrophage-driven inflammatory dysregulation in the elderly population.