Systemic Inflammation Modulates Fc Receptor Expression on Microglia during Chronic Neurodegeneration
Abstract
Chronic neurodegeneration is a major worldwide health problem, and it has been suggested that systemic inflammation can accelerate the onset and progression of clinical symptoms. A possible explanation is that systemic inflammation “switches” the phenotype of microglia from a relatively benign to a highly aggressive and tissue-damaging phenotype. The current study investigated the molecular mechanism underlying this microglia phenotype “switching.” We show in mice with chronic neurodegeneration (ME7 prion model) that there is increased expression of receptors that have a key role in macrophage activation and associated signaling pathways, including TREM-2, Siglec-F, CD200R, and FcγRs. Systemic inflammation induced by LPS further increased protein levels of the activating FcγRIII and FcγRIV, but not of other microglial receptors, including the inhibitory FcγRII. In addition to these changes in receptor expression, IgG levels in the brain parenchyma were increased during chronic neurodegeneration, and these IgG levels further increased after systemic inflammation. γ-Chain–deficient mice show modified proinflammatory cytokine expression in the brain after systemic inflammation. We conclude that systemic inflammation during chronic neurodegeneration increases the expression levels of activating FcγR on microglia and thereby lowers the signaling threshold for Ab-mediated cell activation. At the same time, IgG influx into the brain could provide a cross-linking ligand resulting in excessive microglia activation that is detrimental to neurons already under threat by misfolded protein.
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Other Fc receptors were found to be expressed in microglia, the brain-resident macrophages.
“Even though the expression of FCRL5 within the brain has not yet been reported, other Fc receptors were found to be expressed in microglia, the brain-resident macrophages.60”
From APOE*E2 allele delays age of onset in PSEN1 E280A Alzheimer’s disease (2016) · cites this paper as [60]
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- Authors
- Lunnon, K., Teeling, J. L., Tutt, A. L., Cragg, M. S., Glennie, M. J., & Perry, V. H.
- Affiliations
- King's College London (GB)
- University of Southampton (GB)
- Southampton General Hospital (GB)
- Corresponding author
- Lunnon, Katie
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-06
- Volume
- 186
- Issue
- 12
- Pages
- 7215-7224
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W1919971299
- Cited by
- 138
- References
- 56
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 19 · 2023: 2 · 2022: 9 · 2021: 11 · 2020: 3 · 2019: 5 · 2018: 10 · 2017: 13 · 2016: 9 · 2015: 12 · 2014: 7 · 2013: 15 · 2012: 11
- FWCI
- 6.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- Biogen
- Wellcome Trust
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Prion Diseases and Protein Misfolding
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- systemic inflammation, microglia, chronic neurodegeneration, Fc gamma receptor, FcγRIII, FcγRIV, FcγRII, TREM2, Siglec-F, CD200R, lipopolysaccharide, IgG, inflammatory cytokines, microglial activation, prion disease, neuroinflammation
- MeSH terms
- Antibodies, Chronic Disease, Inflammation, Macrophage Activation, Nerve Degeneration, Phenotype, Receptors, Fc, Signal Transduction, Up-Regulation, Microglia, Disease Progression
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