The lipid transporters localized in the Axolotl foamy macrophages were CD36 and TLR4, the primary transporter and co-transporter used by mammalian foamy macrophages [Figure 6; (75)]. the regenerating cord (1C17). The role of a meningeal reaction in urodele spinal cord regeneration has a far less extensive body of work (5, 12, 13). The present research explores aspects of the urodele spinal meninges response complementary to the earlier studies. Meningeal fibrosis occurs after penetrating spinal cord injury (SCI) in urodele amphibians (newts and salamanders), as it does in mammals [rev. (10, 15)]. Penetrating mammalian SCI induces a meningeal (fibrotic) scar that inhibits axonal regrowth directly and reinforces the astrocytic (gliotic) scar (18, 19). This dual scarring process forms a permanent barrier to axonal regrowth. In urodeles, fibrotic meninges is remodeled and excluded to the periphery of regenerating cord, a process that involves ependymal outgrowth and digestion of extracellular matrix (10, 12, 15, 20). Stensaas (5) and Zukor et al. (12) showed an intimate association of reactive meninges with multiple cell types in transected newt spinal cord. Reactive newt meninges and cord outgrowth were shown to contain macrophages that contact regenerating neurons and ependymoglia during the regenerative process (12). Foamy macrophages, also known as foam cells, foamy phagocytes or foamy histiocytes, are of monocyte origin and distinguished by the foamy appearance of their extensive lipid inclusions in histological preparations (21, 22). They can fuse into osteoclast-like MNGCs (21, 23, 24). Foamy macrophages can serve as sinks for lipoproteins and myelin fragments in pathological neural conditions, such as multiple sclerosis (21, 25C27). They can be, at least transiently, beneficial in this pathology (22, 27). Foamy macrophages form from monocyte-derived M2-macrophage (anti-inflammatory macrophage) precursors (26, 28, 29). Features of foam cells and include: clusters of lipid inclusions that are phase contrast bright, stain with Oil Red O or the indocarbocyanine dye DiI, production of the cysteine proteinase cathepsin K, activity of the lipid scavenger receptor CD36, uptake of oxidized low density lipoprotein (Ox-LDL), and uptake of myelin Rabbit polyclonal to PHF7 fragments. These features are characteristic of live cell lipid droplets, foam cells and osteoclast-like MNGCs derived from foam cells (21, 25C27, 30C33). In mammalian SCI, foamy macrophages form only within injured spinal cord tissue, where they take up myelin and contribute to a pro-inflammatory environment (34). Accumulation of foamy macrophages has not been shown within injured mammalian spinal meninges (34, 35). Macrophages have been described within injured salamander spinal cord, as well, and many immune responsive genes are upregulated shortly after Axolotl SCI (12, 36, 37). However, foamy macrophages have not previously been reported in salamander cord or meninges. Uptake of the toxic lipid metabolites after neural injury can be approximated by uptake of Ox-LDL (38). A common lipid transport mechanism involved in the uptake of Ox-LDL uses CD36, a class B scavenger receptor/fatty acid translocase (25, 39). In atherosclerosis and other pathological conditions, CD36 and Toll-like Receptor-4 (TLR4), along with TLR6, act together in lipid uptake and inflammatory behavior (40). CD 36 is also involved in fusion of Tenofovir Disoproxil Fumarate macrophages to form MNGCs (23, 24). These studies suggest the use of an Ox-LDL uptake model and examination of the role of CD36 in Axolotl meningeal foam cell lipid transport. In many neural pathologies, foamy macrophages and MNGCs also take up myelin sheath products by phagocytosis. Myelin debris persists for extended periods in mammalian spinal cord lesion sites and is sequestered in Tenofovir Disoproxil Fumarate macrophages (41, 42). Extensive myelin fragment uptake by foamy macrophages occurs within active and chronic-active plaques in the CNS in multiple sclerosis (25C27, 43). In animal models of amyotrophic lateral sclerosis, foamy macrophages are involved in myelin uptake during Wallerian degeneration in the peripheral nerves, associated with loss of axons and neuromuscular synapses (44C46). In Charcot-Marie-Tooth disease, a group of peripheral nervous system (PNS) demyelinating disorders, foamy macrophages with myelin Tenofovir Disoproxil Fumarate inclusions are found next to poorly myelinated or Tenofovir Disoproxil Fumarate demyelinated axons (47). Foamy, myelin-containing macrophages are also found in association with peripheral.