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Cited by 13Neuroinflammation and Neurodegeneration MechanismsTryptophan and brain disordersNeuroscience and Neuropharmacology Research

Microglia in systemic neuroimmune communication: functions beyond phagocytosis

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Di Pietro, Anabella Ayelen, Powley, Sharon, Perciballi, Elisa, Stewart, Meredith, Therrien, Martine, Scott-Hewitt, Nicole·2026·Trends in Immunology
DOI 10.1016/j.it.2025.12.002PMC PMC12829908
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Abstract

Bidirectional crosstalk between the immune and nervous systems, via 'neuroimmune circuits', regulates homeostatic and inflammatory responses essential for health. Microglia, long-lived brain macrophages, act as key hubs integrating immune signals into coordinated brain responses by shifting into distinct functional states in response to local and systemic cues. In this review, we focus on how environmental signals shape these microglial states, how microglia influence other brain cells through both direct and indirect mechanisms, and emerging evidence of how microglia are impacted by, and respond to, peripheral changes. We highlight microglia as central players in systemic neuroimmune communication, influencing both brain and peripheral health, while outlining recent tools and key knowledge gaps to guide future research into mechanisms of neuroimmune circuit communication.

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  • During neurodegeneration, blood-brain barrier integrity declines, which may facilitate peripheral monocytes to infiltrate the CNS and differentiate into microglia-like cells.

    “during neurodegeneration, the integrity of the blood–brain barrier declines. This may facilitate debated levels of peripheral monocytes to infiltrate the central nervous system and differentiate into microglia-like cells.”

    From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [25]

    The section “Microglia Bridge Environmental Exposures and CNS Function” (page unavailable) says immune cells can infiltrate during blood–brain barrier disruption. It does not say that barrier integrity declines during neurodegeneration or that infiltrating peripheral monocytes differentiate into microglia-like cells. The “Microglial State-of-Mind” section (page unavailable) instead distinguishes microglia from peripheral infiltrating macrophages. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • Somatic mutations present in the peripheral hematopoietic system could theoretically be imported into the brain's immune environment, posing a mechanistic link between systemic aging and local neuroinflammation.

    “any somatic mutations present in the peripheral hematopoietic system could theoretically be imported into the brain’s immune environment, posing a mechanistic link between systemic aging and local neuroinflammation [10,24,25,26].”

    From Clonal Hematopoiesis of Indeterminate Potential as an Emerging Interdisciplinary Risk Factor in Alzheimer’s Disease: Current Evidence and Future Directions (2026) · cites this paper as [25]

    In “Microglia Bridge Environmental Exposures and CNS Function” (page unavailable), the paper says aging-related systemic inflammation can amplify inflammatory inputs in the CNS and that immune cells can infiltrate during blood–brain barrier disruption. It does not say that peripheral hematopoietic somatic mutations are imported into the brain or identify that as the mechanism linking aging to local neuroinflammation. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

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Authors
Di Pietro, A. A., Powley, S., Perciballi, E., Stewart, M., Therrien, M., & Scott-Hewitt, N.
Affiliations
  • Duke University (US)
  • University of California, Davis (US)
Corresponding author
Therrien, Martine
ORCID
Venue
Trends in Immunology
Publisher
Elsevier BV
Published
2026-06
Volume
47
Issue
6
Pages
495-510
ISSN
1471-4906 (ISSN-L)
DOI
10.1016/j.it.2025.12.002
PMC
PMC12829908
OpenAlex
W7119160483
Cited by
13
References
102
Citations by year
2026: 13
FWCI
9.92
Type
journal article
Language
en
Open access
Licence
Locations
  • Trends in Immunology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Alzheimer's Coordinating Center (T32GM142605)
  • National Institute of General Medical Sciences
  • Alzheimer's Association
  • Cure Alzheimer's Fund
  • Muscular Dystrophy Association
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Neuroscience › Biological Psychiatry › Tryptophan and brain disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
microglia, neuroimmune interactions, neuroimmune circuits, systemic immune response, neuroinflammation, brain macrophages
MeSH terms
Animals, Brain, Cell Communication, Humans, Phagocytosis, Neuroimmunomodulation, Signal Transduction, Microglia

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