Macrophages Settle in the Brain After Sepsis, Driving Memory Loss

Summary:

A study led by the Chinese Academy of Medical Sciences reveals that peripheral immune cells infiltrating the hippocampus during acute sepsis take up permanent residence, driving long-term neuroinflammation and cognitive impairment. These long-lived monocyte-derived macrophages signal through the pleiotrophin (PTN) pathway to provoke resident microglia into abnormally engulfing myelin. Blocking this initial cellular infiltration with the clinical drug natalizumab prevented chronic memory deficits in mice, identifying a critical therapeutic window.

Key Facts:

Permanent Infiltration: Dual-color GFP bone marrow tracking showed that peripheral CCR2+ macrophages entering the hippocampus during acute sepsis do not clear after systemic recovery; they adapt, survive, and remain embedded six months later.
Pathological Cross-Talk: The persistent macrophages release pleiotrophin (PTN), which binds to alpha-beta2 (CD11b) receptors on resident microglia, driving abnormal microglial phagocytosis and the degradation of hippocampal myelin.
Preventative Window: Blocking early leukocyte extravasation with natalizumab during the acute infection phase prevented the establishment of the persistent macrophage population and rescued working, recognition, and spatial memory six months later.

Source: Chinese Academy of Medical Sciences

Severe systemic infections such as sepsis can be successfully managed in intensive care units, yet millions of survivors are left with debilitating long-term consequences. Months or years after the primary infection resolves and systemic inflammation subsides, patients frequently suffer from persistent cognitive impairment, characterized by brain fog, compromised memory, and reduced learning capacity.

While clinicians have long recognized post-sepsis cognitive decline, the precise cellular mechanisms that sustain chronic neuroinflammation after the blood-brain barrier heals have remained a biological mystery.

Now, a comprehensive study led by Professor Qi Xu at the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, uncovers the cellular culprit behind this chronic damage.

Publishing in the journal Immunity & Inflammation, the research team combined single-cell transcriptomics, bone marrow chimera lineage tracing, functional cellular assays, and post-mortem human brain tissue analyses to demonstrate that peripheral immune cells entering the brain during acute infection establish a permanent, destructive niche.

The Discovery of Permanent Brain Invaders

Using a clinically relevant mouse model of sepsis (cecal ligation and puncture), the researchers evaluated brain function six months post-infection, long after the initial systemic crisis had resolved and blood-brain barrier permeability had returned to normal. Despite physiological recovery, the surviving mice showed persistent deficits across spatial learning, working memory, and novel object recognition.

Single-cell RNA sequencing of the hippocampus revealed an altered immune microenvironment populated by two distinct myeloid classes: resident microglia exhibiting hyperactive phagocytic states and foreign, CCR2-positive monocyte-derived macrophages.

To trace the precise origin of these cells, the researchers generated green fluorescent protein (GFP) bone marrow chimeric mice. Tracking these bone marrow-derived cells at 3 days, 1 month, and 6 months post-sepsis confirmed that peripheral macrophages breaching the hippocampus during the acute surge did not clear away. Instead, they down-regulated inflammatory markers like MHCII and Ly6C, adapted to the neural tissue, and embedded themselves as a permanent resident population.

Dual-color bone marrow transplantation confirmed this dynamic: the brain almost exclusively retained green-labeled cells that entered during the acute phase, showing zero recruitment of red-labeled cells from later stages. The chronic population was established entirely during the initial infection window.

Pleiotrophin Signaling Provokes Myelin Destruction

Once embedded, how do these long-lived peripheral cells disrupt cognition?

Ligand-receptor communication modeling identified intense cross-talk between the persistent CCR2-positive macrophages and neighboring microglia. At the center of this signaling was pleiotrophin (PTN), a neurotrophic cytokine heavily enriched in the invading macrophages, and its receptor, the integrin alphabeta2 (CD11b/Itgam), which was strongly upregulated on resident microglia.

Under inflammatory stimulation, macrophage-derived PTN bound to microglial CD11b, driving downstream expression of stress and activation genes, including Jun, Atf3, and Ccl3. This abnormal signaling cascade provoked microglia to excessively engulf and degrade nearby myelin sheaths—the protective insulation coating neural axons.

High-resolution tissue imaging verified the consequence: persistent macrophages were situated directly alongside activated Iba1-positive myeloid cells showing significantly increased internalization of myelin basic protein (MBP).

Early Intervention Rescues Long-Term Memory

Because these long-lived macrophages enter during the acute crisis, the researchers investigated whether blocking their initial entry could protect the brain long term.

The team administered natalizumab, a monoclonal antibody targeting alpha4 integrin-mediated extravasation, on days 0, 3, and 6 following sepsis induction. Mice were then monitored for six months without further treatment.

The early, short-course therapy delivered lasting neuroprotection:

Prevented Infiltration: Natalizumab significantly reduced the accumulation of long-lived GFP-positive macrophages in the hippocampus.
Rescued Cognitive Performance: Treated mice performed normally in Y-maze, novel object recognition, and Barnes maze cognitive evaluations at six months.

Validation in Human Brain Tissue

To confirm whether these findings translate to human pathology, the team evaluated hippocampal tissue from 24 human autopsy cases.

Brain tissue from patients with a documented history of severe systemic infection exhibited a significantly higher density of CD74-positive, TMEM119-negative cells compared to uninfected controls. These cells were clustered tightly around CD31-labeled cerebral blood vessels, exhibiting the identical phenotypic and spatial characteristics of infiltrating peripheral macrophages observed in the mouse models.

“This study links acute infection to long-term brain functional changes through a population of persistent peripheral immune cells, providing a new cellular basis for understanding post-infection cognitive impairment,” the authors concluded.

By defining the acute temporal window when peripheral leukocytes establish residency, the findings demonstrate that protecting the brain during severe infection may require early, targeted anti-migratory interventions to prevent lifelong cognitive decline.

Editorial Notes:

This article was edited by a Neuroscience News editor.
Journal paper reviewed in full.
Additional context added by our staff.

About this neuroscience Research:

Media Contact: Shuo Liu
Source: Immunity & Inflammation
Image Credit: Image credited to GerryShaw
Original Research is 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

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 MHCII^low/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.