CD300f immunoreceptor contributes to peripheral nerve regeneration by the modulation of macrophage inflammatory phenotype

Abstract

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.

Gene expression analysis at multiple time-points identifies key genes for nerve regeneration

“…Wallerian degeneration (WD) results in distal stump degeneration after nerve injury. It is indispensable to subsequent nerve regeneration and is an acute and transient pathological reaction to nerve damage in the PNS . Histologically, WD induces axonal degeneration, demyelination, proliferation of glial cells, and structural loss of the cytoskeleton .…”

“…Macrophages have opposite effects at various time‐points. Resident macrophages are central to potentiating inflammation, whereas infiltrated macrophages have an anti‐inflammatory function . In addition, various factors that contribute to WD have been detected.…”

FGF9 modulates Schwann cell myelination in developing nerves and induces a pro‐inflammatory environment during injury

“…With the development of the disease after P90, the sciatic nerve damage accelerates. Macrophages are constantly recruited to clear the necrotic debris . Macrophages are activated at different stages to undertake different tasks.…”

“…Macrophages are constantly recruited to clear the necrotic debris. 46 Macrophages are activated at different stages to undertake different tasks. M1-associated macrophages are considered to play a role in regulating inflammation and debris clearance and have been reported to promote apoptosis.…”

CD300 receptor family in viral infections

“…Over the past few years, several publications have highlighted the important role the CD300 family of receptors has in complex biological processes such as phagocytosis, proliferation, and cytokine production [7, 12,13,17,24,25,30,31,39,40], and in a variety of diseases, including autoimmune disorders, allergic and inflammatory diseases, hematological malignancies, sepsis, etc. [7,12,17,19,21,33,[41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58]. Here, we review several aspects involving the CD300 molecules and viral infections, including how viruses use these receptors to interact with and enter cells or to escape from the attack of the immune system.…”