Acute sepsis seeds long-lived brain-resident macrophages that drive microglia-dependent chronic neuroinflammation through PTN signaling

Abstract

Early-life severe infection is increasingly recognized as a cause of persistent cognitive impairment; however, the mechanisms by which peripheral immune cells drive and sustain chronic neuroinflammation remain poorly understood. Although infiltrating peripheral myeloid cells are generally considered transient populations that are rapidly cleared upon disease resolution, their long-term fate and contribution to chronic neurological sequelae remain undefined. Here, using a murine model of polymicrobial sepsis, we demonstrate that central nervous system (CNS)-infiltrating macrophages can establish long-term residence and persistently remodel the hippocampal immune microenvironment. Single-cell RNA sequencing revealed a distinct MHCIIlow/Ly6C+ macrophage subpopulation that infiltrates the brain following sepsis and persists for at least six months. Dual-color bone marrow chimera experiments demonstrated that this infiltration is strictly restricted to the acute inflammatory phase, thereby seeding a long-lived resident population. Mechanistically, these macrophages drive microglial phagocytic activation and subsequent myelin damage via the pleiotrophin (PTN) signaling pathway. Importantly, blocking CNS macrophage infiltration during the acute phase of sepsis with a monoclonal antibody targeting alpha 4 beta 1 (α4β1) integrin substantially prevented chronic neuroinflammation and late-stage cognitive impairment. Consistent with these murine findings, a phenotypically similar population of CD74+/TMEM119− infiltrating macrophages was identified in postmortem hippocampal tissues from individuals with a history of severe systemic infection. Collectively, this study redefines the fate of brain-infiltrating macrophages following systemic infection, revealing them not as transient effectors, but rather as a long-lived cellular substrate that perpetuates chronic neuroinflammation. These findings provide a novel mechanistic framework for postinfectious cognitive decline and highlight acute-phase α4β1 integrin blockade as a viable therapeutic strategy for preventing long-term neurological sequelae.