SPP1+ Macrophages are Implicated in Numerous Age-Related Conditions
The innate immune cells known as macrophages are found everywhere in the body, outside the brain. Inside the brain an analogous population known as microglia exists. A population of monocytes resides in the spleen and circulates in the bloodstream, capable of differentiating into macrophages and entering tissues when needed. But large numbers of tissue resident macrophages also exist, already in place. Macrophages undertake a wide range of tasks, including the destruction of infectious pathogens and senescent and cancerous cells, coordination of tissue regeneration following injury, and clearance of metabolic waste and debris. Macrophages are diverse in the sense that they can adopt different programs of expression and behavior in response to circumstances and environment. With advancing age, some of these behaviors can become maladaptive in response to the damaged tissue environment.
Today's open access paper is focused on one specific population of macrophages that is implicated as a source of inflammatory signaling in aging. Chronic inflammation is a feature of aging, with many contributing causes. When inflammation continues indefinitely without resolution, it changes cell behavior to cause disruption to tissue structure and function, contributing to the onset and progression of a range of age-related conditions. Since necessary short term inflammation and harmful long-term inflammation are governed by the same regulatory pathways, it is likely that the only truly effective solution to the problem of chronic inflammation in aged tissues involves removing the molecular damage that provokes it and either removing or altering the behavior of the immune cell populations that generate the largest amounts of inflammatory signaling.
SPP1 macrophages across diseases: A call for reclassification?
Recent advances in macrophage biology have revealed a remarkable diversity among these immune cells, highlighting the existence of specialized subpopulations with distinct functional roles in health and disease. Among these, SPP1+ macrophages, characterized by elevated osteopontin (SPP1) expression, have garnered significant attention due to their consistent association with pathological states. Originally identified in cancer as tumor-associated macrophages (TAMs), SPP1+ macrophages have since been implicated in various conditions, including aging, chronic inflammatory disorders, neurodegenerative diseases, and tissue remodeling.
Aging presents a compelling context in which SPP1+ macrophages emerge as key players. Single-cell RNA sequencing studies have revealed their abundance in the skeletal muscle of aged mice, where they exhibit hallmarks of senescence and enhanced angiogenic and lipid metabolic activity. Beyond musculoskeletal systems, SPP1+ macrophages also influence neurodegenerative diseases. In Alzheimer's disease, an upregulation of SPP1-positive microglia correlates with inflammation and synaptic loss. Perivascular macrophages with SPP1 profiles modulate microglial phagocytic activity, offering a potential mechanism underlying synapse degradation. This dual contribution to inflammation and neurodegeneration positions SPP1+ macrophages as central figures in aging-related pathologies.
Their conserved traits, such as promoting fibrosis, remodeling the extracellular matrix, and modulating immune responses, suggest they play a pivotal role in sustaining chronic inflammation and tissue dysfunction. Furthermore, their presence often correlates with poor clinical outcomes, underscoring their relevance as potential therapeutic targets. Despite these shared characteristics, SPP1+ macrophages exhibit functional adaptability across different disease contexts, raising questions about their classification and the underlying mechanisms that drive their diverse roles.
In this perspective, we briefly summarize recent discoveries on the multifaceted roles of SPP1+ macrophages across various pathological conditions, emphasizing their shared traits and the critical differences dictated by the tissue microenvironment and pathological inflammatory context. Based on our comparative literature investigation, we also propose a re-evaluation of their classification, advocating for their recognition as a distinct macrophage subtype linked to prolonged inflammatory states rather than specific to tumors. Such a shift in perspective could not only advance our understanding of macrophage biology but also open new avenues for targeted therapeutic interventions.