Fibrinogen-induced perivascular microglial clustering is required for the development of axonal damage in neuroinflammation
Open accessAbstract
Blood-brain barrier disruption, microglial activation and neurodegeneration are hallmarks of multiple sclerosis. However, the initial triggers that activate innate immune responses and their role in axonal damage remain unknown. Here we show that the blood protein fibrinogen induces rapid microglial responses toward the vasculature and is required for axonal damage in neuroinflammation. Using in vivo two-photon microscopy, we demonstrate that microglia form perivascular clusters before myelin loss or paralysis onset and that, of the plasma proteins, fibrinogen specifically induces rapid and sustained microglial responses in vivo. Fibrinogen leakage correlates with areas of axonal damage and induces reactive oxygen species release in microglia. Blocking fibrin formation with anticoagulant treatment or genetically eliminating the fibrinogen binding motif recognized by the microglial integrin receptor CD11b/CD18 inhibits perivascular microglial clustering and axonal damage. Thus, early and progressive perivascular microglial clustering triggered by fibrinogen leakage upon blood-brain barrier disruption contributes to axonal damage in neuroinflammatory disease. Multiple sclerosis is characterized by the activation of microglia cells. Davalos et al. investigate the early stages of neuroinflammation in mice and reveal that the plasma protein fibrinogen induces microglial clustering around the brain vasculature, which facilitates lesion formation and focal axonal damage.
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Fibrinogen and its polymeric form fibrin can activate integrin receptors on glial cells and neurons to inhibit regeneration, or receptors on microglia and bone-derived macrophages to exacerbate neuroinflammation and induce antigen-presenting genes.
“For example, fibrinogen and its polymeric form fibrin can activate integrin receptors on glial cells and neurons to inhibit regeneration (45, 522), or receptors on microglia and bone-derived macrophages to exacerbate neuroinflammation and induce antigen-presenting genes (45, 132, 510).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [132]
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredDepleting fibrinogen and/or preventing its accumulation in the brain with ancrod attenuated both neuroinflammation and vascular pathology in Alzheimer's disease mice and in a multiple sclerosis model.
“Depleting fibrinogen and/or preventing its accumulation in the brain, as for example with ancrod, a defibrinogenating agent, attenuated both neuroinflammation and vascular pathology in AD mice (467) and in an MS model (132).”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [132]
For the MS-model portion of the sentence, the Results section ('Fibrin is required for perivascular microglial clustering'; page unavailable) reports that hirudin reduced perivascular microglial clustering, fibrin deposition, and demyelination in EAE mice. The paper used hirudin, not ancrod, and does not establish an improvement in vascular pathology beyond reduced fibrin deposition. The separate AD-mouse claim is attached to citation 467, not this source. (LLM, conf=0.86)
Experimental — accuracy not yet measuredClonal hematopoiesis (CH) prominently involves variants of epigenetic regulatory genes, such as DNMT3A and TET2.
“CH prominently involves variants of epigenetic regulatory genes, such as DNMT3A and TET2, which constitute an increased risk for hematologic malignancies, cardiovascular events and stroke 34,45,70,71 .”
From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [70]
The Results section discusses fibrinogen signaling, microglial clustering, and axonal damage in neuroinflammation (page unavailable). Searches for clonal hematopoiesis, DNMT3A, TET2, and epigenetic regulatory genes found no passage in our copy addressing the attributed claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredCH variants such as DNMT3A and TET2 constitute an increased risk for hematologic malignancies, cardiovascular events and stroke.
“CH prominently involves variants of epigenetic regulatory genes, such as DNMT3A and TET2, which constitute an increased risk for hematologic malignancies, cardiovascular events and stroke 34,45,70,71 .”
From Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice (2025) · cites this paper as [70]
The Results section on fibrin signaling via CD11b/CD18 addresses microglial clustering and axonal damage in neuroinflammation, not clonal hematopoiesis. Searches for DNMT3A, TET2, clonal hematopoiesis, hematologic malignancies, cardiovascular events, and stroke found no passage in our copy addressing the claimed risks; page numbers were not provided. (LLM, conf=0.78)
Experimental — accuracy not yet measuredFibrinogen induces activation of microglia and consequently release of ROS, inducing axonal damage.
“In this event, fibrinogen induces the activation of microglia and consequently the release of ROS, inducing axonal damage (Davalos et al., 2012).”
From The impact of microglial activation on blood-brain barrier in brain diseases (2014) · cites this paper as Davalos et al., 2012
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“Other substances that induce microglial chemotaxis in vivo are NO (in the white matter (24)) and fibrinogen (25), which can leak from damaged blood vessels.”
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- Authors
- Davalos, D., Kyu Ryu, J., Merlini, M., Baeten, K. M., Le Moan, N., Petersen, M. A., Deerinck, T. J., Smirnoff, D. S., Bedard, C., Hakozaki, H., Gonias Murray, S., Ling, J. B., Lassmann, H., Degen, J. L., Ellisman, M. H., & Akassoglou, K.
- Affiliations
- University of California, San Francisco (US)
- University of California San Diego (US)
- Medical University of Vienna (AT)
- Cincinnati Children's Hospital Medical Center (US)
- Corresponding author
- Akassoglou, Katerina
- ORCID
- Venue
- Nature Communications
- Published
- 2012-11-27
- Volume
- 3
- Issue
- 1
- Pages
- 1227-1227
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC3514498
- OpenAlex
- W2125281412
- Cited by
- 568
- References
- 61
- Citations by year
- 2026: 28 · 2025: 38 · 2024: 58 · 2023: 50 · 2022: 50 · 2021: 53 · 2020: 45 · 2019: 33 · 2018: 29 · 2017: 34 · 2016: 40 · 2015: 46 · 2014: 41 · 2013: 23
- FWCI
- 17.70
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-sa
- www.springer.com/tdm (unspecified)
- Locations
- Nature Communications (publishedVersion, cc-by-nc-sa)
- PubMed Central (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Multiple Sclerosis Society
- March of Dimes Foundation (4-FY10-461)
- American Heart Association
- Nancy Davis Foundation for Multiple Sclerosis
- Gladstone Institutes (RR18928)
- Multiple Sclerosis Society
- H. Lundbeck A/S
- National Institutes of Health (1c06rr018928-01, CA082103, RR004050)
- University of California, San Francisco
- National Heart, Lung, and Blood Institute (HL096126, R01HL096126)
- National Cancer Institute (CA-082103, P30CA082103)
- National Institute of Neurological Disorders and Stroke (NS051470, R01NS066361, NS052189, NS066361, R01NS052189, R01NS051470)
- National Center for Research Resources (P41RR004050, RR004050, C06-RR-018928, RR18928)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD000850)
- Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- fibrinogen, perivascular microglia, axonal injury, neuroinflammation, multiple sclerosis, blood-brain barrier disruption, microglial activation, reactive oxygen species, CD11b/CD18 integrin, fibrin formation, plasma protein leakage, demyelination
- MeSH terms
- Animals, Axons, Blood-Brain Barrier, Encephalomyelitis, Autoimmune, Experimental, Female, Fibrin, Fibrinogen, Mice, Inbred C57BL, Spinal Cord, Reactive Oxygen Species, Microglia, Microscopy, Fluorescence, Multiphoton, Mice
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