Summary:
A study led by the Chinese Academy of Medical Sciences shows that peripheral immune cells that enter the hippocampus during acute sepsis can become long-lived residents, driving chronic neuroinflammation and lasting cognitive deficits. These monocyte-derived macrophages persistently produce pleiotrophin (PTN), activating resident microglia through alpha-beta2 (CD11b) signaling and provoking abnormal myelin engulfment. Preventing the initial leukocyte entry with the clinical drug natalizumab during the acute infection phase averted long-term memory impairment in mice, revealing a critical early therapeutic window.
Key Facts:
- Permanent Infiltration: Dual-color GFP bone marrow tracking demonstrated that CCR2+ macrophages entering the hippocampus during acute sepsis do not disappear after systemic recovery; they adapt to the neural environment and persist for at least six months.
- Pathological Cross-Talk: Persistent macrophages secrete pleiotrophin (PTN), which engages CD11b on microglia, triggering aberrant microglial phagocytosis and progressive myelin degradation in the hippocampus.
- Preventative Window: Early blockade of leukocyte extravasation with natalizumab during acute infection prevented establishment of the persistent macrophage population and rescued spatial, working, and recognition memory at six months.
Source: Chinese Academy of Medical Sciences
Severe systemic infections such as sepsis are increasingly survivable in intensive care units, yet many survivors experience long-term neurological consequences. Months or years after the initial infection resolves and systemic inflammation subsides, patients commonly report persistent cognitive problems—brain fog, memory loss, and reduced learning capacity.
Although clinicians have recognized post-sepsis cognitive decline for years, the exact cellular mechanisms that sustain chronic brain inflammation once the blood-brain barrier has healed remained unclear.
A comprehensive study led by Professor Qi Xu at the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, identifies a cellular mechanism linking acute systemic infection to long-lasting cognitive dysfunction.
Published in the journal Immunity & Inflammation, the team combined single-cell transcriptomics, bone marrow chimera lineage tracing, functional assays, and analyses of postmortem human hippocampal tissue to show that peripheral immune cells that infiltrate the brain during acute sepsis can form a permanent, destructive niche.
The Discovery of Permanent Brain Invaders
Using a clinically relevant mouse model of sepsis (cecal ligation and puncture), researchers assessed hippocampal function six months after infection, well beyond the period of systemic recovery and restoration of blood-brain barrier integrity. Despite physiological recovery, mice displayed persistent impairments in spatial learning, working memory, and novel object recognition.
Single-cell RNA sequencing of hippocampal tissue revealed a remodeled immune microenvironment composed of two distinct myeloid populations: resident microglia in hyperactive phagocytic states and infiltrating CCR2-positive monocyte-derived macrophages.
To determine cellular origin, the team generated GFP bone marrow chimeric mice and followed bone marrow–derived cells at 3 days, 1 month, and 6 months after sepsis. Peripheral macrophages that breached the hippocampus during the acute inflammatory surge did not clear; instead, they downregulated inflammatory markers such as MHCII and Ly6C, adapted to the neural niche, and remained embedded as a long-lived population.
Dual-color bone marrow transplantation confirmed that the hippocampus retained predominantly the cells that entered during the acute phase, with virtually no later recruitment. The chronic macrophage population was established exclusively during the initial infection window.
Pleiotrophin Signaling Provokes Myelin Destruction
How do these long-lived peripheral macrophages disrupt cognition once resident in the brain?
Ligand–receptor interaction modeling revealed intense communication between persistent CCR2-positive macrophages and neighboring microglia. Central to this cross-talk was pleiotrophin (PTN), a cytokine enriched in the infiltrating macrophages, and its receptor integrin alpha-beta2 (CD11b/Itgam), highly expressed on microglia.
Under inflammatory conditions, macrophage-derived PTN engages microglial CD11b, driving expression of stress and activation genes such as Jun, Atf3, and Ccl3. This signaling cascade induces microglia to over-engulf nearby myelin sheaths—the insulating layers around axons—leading to myelin loss and impaired neural circuitry.
High-resolution tissue imaging confirmed that persistent macrophages are positioned alongside activated Iba1-positive myeloid cells, which show markedly increased internalization of myelin basic protein (MBP).
Early Intervention Rescues Long-Term Memory
Because the persistent macrophages enter the brain during the acute infection phase, the researchers tested whether blocking their initial entry would protect cognitive function in the long term.
Mice received natalizumab, a monoclonal antibody that inhibits α4 integrin–mediated leukocyte extravasation, on days 0, 3, and 6 after sepsis induction, and were observed for six months without further treatment.
A brief early treatment provided lasting benefit:
- Prevented Infiltration: Natalizumab markedly reduced accumulation of long-lived GFP-positive macrophages in the hippocampus.
- Rescued Cognition: Treated mice performed comparably to controls in Y-maze, novel object recognition, and Barnes maze tests at six months.
Validation in Human Brain Tissue
To evaluate translational relevance, the investigators analyzed hippocampal tissue from 24 human autopsy cases. Individuals with documented histories of severe systemic infection had significantly higher densities of CD74-positive, TMEM119-negative cells compared with controls. These cells clustered near CD31-labeled blood vessels and matched the phenotype and spatial pattern of the infiltrating peripheral macrophages seen in mice.
“This study connects acute infection to lasting brain dysfunction via a population of persistent peripheral immune cells, offering a cellular basis for post-infection cognitive impairment,” the authors concluded.
By identifying the acute temporal window when peripheral leukocytes seed the brain, these findings suggest that early, targeted anti-migratory interventions during severe infection may be necessary to prevent lifelong cognitive decline.
Editorial Notes:
- Edited by a Neuroscience News editor.
- Primary research article reviewed in full.
- Additional explanatory context added by staff.
About this neuroscience Research:
- Media Contact: Shuo Liu
- Source: Immunity & Inflammation
- Image Credit: Image credited to GerryShaw
- Original Research (Open Access): Immunity & Inflammation (Oct 1, 2026). “Acute sepsis seeds long-lived brain-resident macrophages that drive microglia-dependent chronic neuroinflammation through PTN signaling.” Authors: Erning Zhang, Longze Sha, Caiyun Zhu, Ziqun Zhou, Zhongman Jin, Xiaolin Yu, Peixin Meng, Kexin Meng, Hui Wei & Qi Xu.
- DOI: 10.1007/s44466-026-00054-0
Abstract
Acute sepsis seeds long-lived brain-resident macrophages that drive microglia-dependent chronic neuroinflammation through PTN signaling
Severe early-life infection is increasingly recognized as a driver of persistent cognitive impairment, but the mechanisms by which peripheral immune cells sustain chronic neuroinflammation are not fully defined. Infiltrating peripheral myeloid cells are often assumed to be transient and cleared after disease resolution, leaving their long-term fate and role in chronic neurological sequelae unclear.
Using a murine polymicrobial sepsis model, this study shows that CNS-infiltrating macrophages can take long-term residence in the hippocampus and chronically reshape its immune microenvironment.
Single-cell RNA sequencing identified a distinct MHCIIlow/Ly6C+ macrophage subset that invades the brain following sepsis and persists for at least six months. Dual-color bone marrow chimera experiments established that this seeding is confined to the acute inflammatory phase, producing a durable resident population.
Mechanistically, these macrophages drive microglial phagocytic activation and subsequent myelin damage through pleiotrophin (PTN) signaling. Critically, blocking CNS macrophage entry during the acute sepsis phase with an antibody targeting α4β1 integrin substantially reduced chronic neuroinflammation and late cognitive deficits.
Parallel analyses of postmortem human hippocampal tissue revealed a phenotypically similar CD74+/TMEM119− infiltrating macrophage population in individuals with histories of severe systemic infection. Together, these results redefine the post-infection fate of brain-infiltrating macrophages, identifying them as a lasting cellular substrate that perpetuates chronic neuroinflammation and a potential therapeutic target during the acute infection window.