A study led by Professor Qi Xu at the Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, was published in Volume 2 of the journal Immunity & Inflammation on September 29, 2026. The article combines single-cell transcriptomics, bone marrow chimera tracking, functional cell experiments, and human brain tissue analysis to reveal the long-term fate of peripheral immune cells in the brain after infection.
Severe infection can be controlled, but many sepsis survivors continue to experience memory loss and reduced learning ability. For these patients, surviving the acute phase does not mean that brain function has recovered. What sustains chronic neuroinflammation after systemic infection resolves has remained unclear.
To address this question, the researchers established a mouse model of sepsis using cecal ligation and puncture. Six months after infection, when blood–brain barrier permeability had returned to normal, surviving mice still exhibited deficits in working memory, recognition memory, and spatial learning. Single-cell transcriptomic analysis of the hippocampus revealed persistent alterations in the immune microenvironment. The hippocampus was enriched with Ccr2-positive monocyte-derived macrophages and microglia with phagocytosis-related features. The former displayed a long-term residency transcriptional signature, while the latter upregulated genes related to myelin processing, phagocytosis, and stress responses. These findings suggested that peripherally derived cells and resident brain immune cells jointly contribute to chronic pathology after infection.
Where did these macrophages come from? The team generated GFP bone marrow chimeric mice and tracked bone marrow-derived cells at 3 days, 1 month, and 6 months after sepsis induction. Immunofluorescence showed that GFP-positive cells entering the hippocampus during the acute phase were not completely cleared as infection resolved and remained detectable at 6 months. Longitudinal single-cell analysis identified Ccr2-positive monocyte-derived macrophages, and GFP labeling supported their peripheral origin. The long-lived population was enriched for MHCII-low, Ly6C-positive subsets and transitioned from acute inflammatory states to long-term survival and brain environment adaptation. Dual-color bone marrow transplantation showed that the brain mainly retained green-labeled cells corresponding to the acute phase, with no red-labeled cells from later transplantation detected. This supported the conclusion that the long-lived population was primarily established by cells that entered the brain during the acute phase.
How do these long-lived macrophages influence the brain immune environment? Cell–cell communication analysis revealed strong interactions between Ccr2-positive macrophages and phagocytosis-related microglia, with the pleiotrophin pathway ranking among the top inferred outgoing signals from macrophages. Ptn expression was enriched in macrophages, while Itgam expression was elevated in phagocytosis-related microglia. Consistent with these communication clues, phagocytosis-related microglia upregulated multiple genes involved in myelin processing and stress responses. Tissue imaging showed that GFP-positive infiltrating cells were adjacent to Iba1-positive myeloid cells, and colocalization of MBP myelin signals with Iba1 signals was increased. Experiments using BV2 cells and primary microglia validated that, under lipopolysaccharide or interferon-gamma stimulation, addition of PTN enhanced expression of Jun , Atf3 , and Ccl3 , and increased phagocytic capacity. CD11b blockade attenuated these effects. These results suggest that PTN–αMβ2 signaling participates in abnormal intercellular communication.
If the long-lived population is established early during infection, can blocking its initial entry into the brain alter long-term outcomes? The researchers targeted α4 integrin-mediated immune cell migration across the blood–brain barrier and administered natalizumab on days 0, 3, and 6 after sepsis induction, followed by assessment at 6 months. Compared with vehicle controls, early intervention reduced GFP-positive cells in the hippocampus and improved performance in the Y maze, novel object recognition, and Barnes maze. The link between short-term early intervention and long-term protection suggests that acute-phase cell entry into the brain may represent a valuable intervention window.
The team further analyzed hippocampal tissue from 24 human autopsy cases. In samples with a history of severe systemic infection, the density of CD74-positive, TMEM119-negative cells was higher than in samples without infection. Age-stratified analysis also showed infection-related differences. Some CD74-positive cells were located near CD31-labeled blood vessels, and their phenotype and spatial distribution were consistent with peripheral macrophage infiltration. This observation provides human brain tissue-level support for the animal findings.
Together, these results support a mechanistic model of chronic post-infection brain immune abnormalities: peripheral macrophages entering the hippocampus during the acute phase form a long-lived resident population; PTN-related signaling in the inflammatory environment enhances microglial phagocytic responses, potentially contributing to abnormal myelin processing and persistent cognitive impairment; early blockade of cell entry shows long-term protection in mice. “ 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, and they further pointed out the future direction: “ Further dissection of how these cells survive long term, how they interact with microglia, and when intervention can balance infection defense and brain protection will help advance mechanistic research and translational exploration. ”
Reference
Title of original paper: Acute sepsis seeds long-lived brain-resident macrophages that drive microglia-dependent chronic neuroinflammation through PTN signaling
Journal: Immunity & Inflammation
DOI: https://doi.org/10.1007/s44466-026-00054-0
About Immunity & Inflammation
Immunity & Inflammation is a newly launched open-access journal co-published by the Chinese Society for Immunology and Springer Nature under the leadership of Editors-in-Chief Prof. Xuetao Cao and Prof. Jules A. Hoffmann. Immunity & Inflammation aims to publish major scientific questions and cutting-edge advances that explore groundbreaking discoveries and insights across the spectrum of immunity and inflammation, from basic science to translational and clinical research.
Website: https://link.springer.com/journal/44466
About Prof. Qi Xu from Chinese Academy of Medical Sciences, China
Dr. Qi Xu is a Tenured Professor at the Chinese Academy of Medical Sciences and Peking Union Medical College. With over 30 years, she has focused on the mechanisms of severe brain diseases such as Alzheimer's disease and novel drug development. Her research has advanced understanding of glial cells and excitotoxicity and supported drug target discovery and Class I drug research. She has led multiple national projects, including those funded by the National Natural Science Foundation of China. Her honors include the Chang Jiang Scholar Distinguished Professor recognition, National Ten Thousand Talents Program designation, China Youth Science and Technology Award, the China Young Women Scientists Award, and the National May 1 Labor Medal.
Funding information
This work was supported by research grants from the National Natural Science Foundation of China (82595940, 82595942, 32293213), the Ministry of Science and Technology of the People’s Republic of China (2021ZD0203001, 2022ZD0211700, 2021ZD0200600, and 2021ZD0202000), the CAMS Innovation Fund for Medical Sciences (2021-I2M-1–020), the Fundamental Research Funds for the Central Universities, Peking Union Medical College and the Peking Union Medical College Education Foundation, STI2030-Major Projects (2021ZD0202001).
Immunity & Inflammation
Experimental study
Animals
Acute sepsis seeds long-lived brain-resident macrophages that drive microglia-dependent chronic neuroinflammation through PTN signaling
29-Sep-2026
The authors declare no competing interests.