BackgroundIt has recently become evident that activating/inhibitory cell surface immune receptors play a critical role in regulating immune and inflammatory processes in the central nervous system (CNS). The immunoreceptor CD300f expressed on monocytes, neutrophils, and mast cells modulates inflammation, phagocytosis, and outcome in models of autoimmune demyelination, allergy, and systemic lupus erythematosus. On the other hand, a finely regulated inflammatory response is essential to induce regeneration after injury to peripheral nerves since hematogenous macrophages, together with resident macrophages and de-differentiated Schwann cells, phagocyte distal axonal and myelin debris in a well-orchestrated inflammatory response. The possible roles and expression of CD300f and its ligands have not been reported under these conditions.MethodsBy using quantitative PCR (QPCR) and CD300f-IgG2a fusion protein, we show the expression of CD300f and its ligands in the normal and crush injured sciatic nerve. The putative role of CD300f in peripheral nerve regeneration was analyzed by blocking receptor-ligand interaction with the same CD300f-IgG2a soluble receptor fusion protein in sciatic nerves of Thy1-YFP-H mice injected at the time of injury. Macrophage M1/M2 polarization phenotype was also analyzed by CD206 and iNOS expression.ResultsWe found an upregulation of CD300f mRNA and protein expression after injury. Moreover, the ligands are present in restricted membrane patches of Schwann cells, which remain stable after the lesion. The lesioned sciatic nerves of Thy1-YFP-H mice injected with a single dose of CD300f-IgG2a show long lasting effects on nerve regeneration characterized by a lower number of YFP-positive fibres growing into the tibial nerve after 10 days post lesion (dpl) and a delayed functional recovery when compared to PBS- or IgG2a-administered control groups. Animals treated with CD300f-IgG2a show at 10 dpl higher numbers of macrophages and CD206-positive cells and lower levels of iNOS expression than both control groups. At later time points (28 dpl), increased numbers of macrophages and iNOS expression occur.ConclusionsTaken together, these results show that the pair CD300f ligand is implicated in Wallerian degeneration and nerve regeneration by modulating both the influx and phenotype of macrophages.
24The increasing incidence of diseases affecting the central nervous system 25 (CNS) demands the urgent development of efficient drugs. While many of 26 these medicines are already available, the Blood Brain Barrier and to a lesser 27 extent, the Blood Spinal Cord Barrier pose physical and biological limitations 28 to their diffusion to reach target tissues. Therefore, efforts are needed not only 29 to address drug development but specially to design suitable vehicles for 30 delivery into the CNS through systemic administration. In the context of the 31 functional and structural versatility of proteins, recent advances in their 32 biological fabrication and a better comprehension of the physiology of the 33 CNS offer a plethora of opportunities for the construction and tailoring of plain 34 nanoconjugates and of more complex nanosized vehicles able to cross these 35 barriers. We revise here how the engineering of functional proteins offer drug 36 delivery tools for specific CNS diseases and more transversally, how proteins 37 can be engineered into smart nanoparticles or 'artificial viruses' to afford 38 therapeutic requirements through alternative administration routes. 39 40 41
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