Loss of the receptor tyrosine kinase Axl leads to enhanced inflammation in the CNS and delayed removal of myelin debris during Experimental Autoimmune Encephalomyelitis

Abstract

BackgroundAxl, 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.MethodsWT 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.ResultsAxl-/- 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.ConclusionsThese 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.

MerTK Is a Functional Regulator of Myelin Phagocytosis by Human Myeloid Cells

“…In addition, direct administration of recombinant human Gas6 into the CNS in this model resulted in enhanced debris clearance, remyelination, and axonal survival (37). High levels of soluble MerTK and Axl have been detected in MS lesions correlating with low levels of Gas6, suggesting that these soluble TAM receptors may sequester Gas6 and thereby inhibit the phagocytic capacity of lesion-associated myeloid cells (38).…”

Erythrocyte efferocytosis modulates macrophages towards recovery after intracerebral hemorrhage

“…The contribution of MDMs to hematoma resolution and the effect on disease progression requires further investigation in other models. AXL and MERTK function are critical to immune homeostasis (20) and have been shown to promote immunoregulatory functions in infection (76), atherosclerosis (28), cancer (77), and autoimmune disease (78). Notably, these receptors have been implicated in controlling inflammatory responses in the CNS, including in multiple sclerosis (79) and Parkinson's disease (55), suggesting that they may direct immune function in a wide range of neurological diseases.…”

Biology of the TAM Receptors

“…TAM mutant mice also display relatively high titers of antibodies to autoantigens, including double-stranded DNA, phospholipids, and ribonucleoproteins (Lu and Lemke 2001;Scott et al 2001;Radic et al 2006). Crossing Mer or Axl mutants into existing mouse models of autoimmune disease has generally been found to exacerbate disease (Weinger et al 2011;Ye et al 2011). , mediated by Toll-like receptors (e.g., TLR4 on the cell surface and TLR3 in endosomes) and other pattern recognition receptors triggers a kinase cascade that leads to the activation of transcription factors (IRF3/7, AP-1, NF-kB) that drive the production of an initial bolus of type I interferons (IFNs) and other proinflammatory cytokines.…”

“…Microglia, the tissue macrophages of the brain, also express Axl and Mer (Gautier et al 2012), and there is evidence that TAM signaling through these receptors controls the phagocytosis of ACs and the inhibition of inflammation in the CNS just as it does in macrophages and DCs in the periphery (Grommes et al 2008;Weinger et al 2011). Tyro3 is also prominently expressed by many CNS neurons (Lai and Lemke 1991;Lai et al 1994;Prieto et al 2000Prieto et al , 2007.…”