Macrophages Polarization as a Potential Driver and a Therapeutic Target for Sepsis-induced Cognitive Impairment in...

Sepsis, a dysregulated host response to infection, remains a growing global health concern, particularly in older adults. While much attention focuses on acute survival, an increasing number of sepsis survivors experience persistent neurological complications, including impairments in memory, attention, and executive function. In severe cases, these may manifest as sepsis-associated delirium or progress to long-term cognitive impairment and dementia. The mechanisms driving these outcomes are complex and incompletely understood, partly due to limited baseline cognitive data and significant variability among older adults. A central feature of sepsis-induced brain dysfunction is sustained neuroinflammation, which bridges peripheral immune activation and central nervous system injury. Mounting evidence implicates macrophages, including circulating monocytes and brain-resident microglia, as key regulators of this neuroimmune axis. Inflammatory conditions during sepsis often drive macrophage polarization toward a pro-inflammatory M1 phenotype, leading to the release of cytokines and reactive oxygen species that exacerbate blood-brain barrier disruption and neuronal injury. Conversely, impaired transition to the M2 phenotype hinders inflammation resolution and tissue repair. Critically, this interaction is bidirectional, where neuroinflammatory signals from activated microglia can influence peripheral macrophage behavior, creating a self-reinforcing inflammatory loop that may prolong central nervous system damage. This process is especially concerning in older adults who may have preexisting immune vulnerabilities and varying baseline cognitive status, which presents unique challenges for therapeutic targeting. This review highlights the central and dynamic role of macrophage polarization in sepsis-associated cognitive decline. Understanding how systemic and neuroinflammatory pathways converge through macrophage signaling may reveal new therapeutic targets to mitigate long-term neurological complications in sepsis survivors. Graphical abstract-Sepsis alters the abundance and polarization of macrophage subpopulations, contributing to both short- and long-term cognitive impairment. In the acute phase, these changes may manifest as sepsis-associated delirium (SAD), while in the long term, sustained immune dysregulation and neuroinflammation may contribute to persistent cognitive deficits, including memory loss and executive dysfunction.