Loss of the receptor tyrosine kinase Axl leads to enhanced inflammation in the CNS and delayed removal of myelin debris during experimental autoimmune encephalomyelitis
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BACKGROUND: Axl, together with Tyro3 and Mer, constitute the TAM family of receptor tyrosine kinases. In the nervous system, Axl and its ligand Growth-arrest-specific protein 6 (Gas6) are expressed on multiple cell types. Axl functions in dampening the immune response, regulating cytokine secretion, clearing apoptotic cells and debris, and maintaining cell survival. Axl is upregulated in various disease states, such as in the cuprizone toxicity-induced model of demyelination and in multiple sclerosis (MS) lesions, suggesting that it plays a role in disease pathogenesis. To test for this, we studied the susceptibility of Axl-/- mice to experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. METHODS: WT and Axl-/- mice were immunized with myelin oligodendrocyte glycoprotein (MOG)35-55 peptide emulsified in complete Freund's adjuvant and injected with pertussis toxin on day 0 and day 2. Mice were monitored daily for clinical signs of disease and analyzed for pathology during the acute phase of disease. Immunological responses were monitored by flow cytometry, cytokine analysis and proliferation assays. RESULTS: Axl-/- mice had a significantly more severe acute phase of EAE than WT mice. Axl-/- mice had more spinal cord lesions with larger inflammatory cuffs, more demyelination, and more axonal damage than WT mice during EAE. Strikingly, lesions in Axl-/- mice had more intense Oil-Red-O staining indicative of inefficient clearance of myelin debris. Fewer activated microglia/macrophages (Iba1+) were found in and/or surrounding lesions in Axl-/- mice relative to WT mice. In contrast, no significant differences were noted in immune cell responses between naïve and sensitized animals. CONCLUSIONS: These data show that Axl alleviates EAE disease progression and suggests that in EAE Axl functions in the recruitment of microglia/macrophages and in the clearance of debris following demyelination. In addition, these data provide further support that administration of the Axl ligand Gas6 could be therapeutic for immune-mediated demyelinating diseases.
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Microglia at both 14 and 21 dpi up-regulated genes critical for the uptake and degradation of cellular and myelin debris, such as Apoe, Clec7a, and Axl.
“Furthermore, microglia at both 14 and 21 dpi up-regulated genes critical for the uptake and degradation of cellular and myelin debris, such as Apoe, Clec7a, and Axl (41–43).”
From Microglia depletion exacerbates demyelination and impairs remyelination in a neurotropic coronavirus infection (2020) · cites this paper as [43]
The Discussion states that Axl is upregulated in EAE, and the Conclusions link Axl to microglia/macrophage recruitment and debris clearance (page numbers unavailable). The paper does not establish that microglia up-regulated Axl at both 14 and 21 dpi, or report the claimed up-regulation of Apoe and Clec7a. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe clearance of myelin debris by microglia is believed to be critically required to limit neuronal damage in EAE.
“In particular, the clearance of myelin debris by microglia is believed to be critically required to limit neuronal damage in EAE (Cignarella et al., 2020; Takahashi et al., 2007; Weinger et al., 2011).”
From SYK coordinates neuroprotective microglial responses in neurodegenerative disease (2022) · cites this paper as Weinger et al., 2011
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- Authors
- Weinger, J. G., Brosnan, C. F., Loudig, O., Goldberg, M. F., Macian, F., Arnett, H. A., Prieto, A. L., Tsiperson, V., & Shafit-Zagardo, B.
- Affiliations
- Albert Einstein College of Medicine (US)
- Amgen (United States) (US)
- Indiana University Bloomington (US)
- Venue
- Journal of Neuroinflammation
- Published
- 2011-05-15
- Volume
- 8
- Issue
- 1
- Pages
- 49-49
- ISSN
- 1742-2094 (ISSN-L)
- PMC
- PMC3121615
- OpenAlex
- W2081982964
- Cited by
- 134
- References
- 57
- Citations by year
- 2026: 9 · 2025: 14 · 2024: 10 · 2023: 9 · 2022: 9 · 2021: 10 · 2020: 15 · 2019: 10 · 2018: 13 · 2017: 5 · 2016: 10 · 2015: 6 · 2014: 9 · 2013: 3 · 2012: 2
- FWCI
- 3.14
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Journal of Neuroinflammation (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Multiple Sclerosis Society
- Multiple Sclerosis Society
- National Institutes of Health
- National Institute of General Medical Sciences (GM 07491, T32GM007491)
- National Institute of Allergy and Infectious Diseases (R01AI059738)
- National Institute of Neurological Disorders and Stroke (R21NS061128)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
- Life Sciences › Immunology and Microbiology › Immunology › Phagocytosis and Immune Regulation
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- AXL receptor tyrosine kinase, TAM receptors, Gas6, experimental autoimmune encephalomyelitis, multiple sclerosis, demyelination, myelin debris clearance, neuroinflammation, myelin oligodendrocyte glycoprotein, axonal injury
- MeSH terms
- Axl Receptor Tyrosine Kinase, Animals, Central Nervous System, Encephalomyelitis, Autoimmune, Experimental, Glycoproteins, Inflammation, Macrophages, Myelin Sheath, Peptide Fragments, Proto-Oncogene Proteins, Cytokines, Microglia, Mice, Knockout, Receptor Protein-Tyrosine Kinases, Mice, Myelin-Oligodendrocyte Glycoprotein
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