Hydrogen peroxide is a neuronal alarmin that triggers specific RNAs, local translation of Annexin A2, and cytoskeletal remodeling in Schwann cells

Abstract

Schwann cells are key players in neuro-regeneration: They sense "alarm" signals released by degenerating nerve terminals and differentiate toward a proregenerative phenotype, with phagocytosis of nerve debris and nerve guidance. At the murine neuromuscular junction, hydrogen peroxide (HO) is a key signal of Schwann cells' activation in response to a variety of nerve injuries. Here we report that Schwann cells exposed to low doses of HO rewire the expression of several RNAs at both transcriptional and translational levels. Among the genes positively regulated at both levels, we identified an enriched cluster involved in cytoskeleton remodeling and cell migration, with the Annexin (Anxa) proteins being the most represented family. We show that both Annexin A2 (Anxa2) transcript and protein accumulate at the tips of long pseudopods that Schwann cells extend upon HO exposure. Interestingly, Schwann cells reply to this signal and to nerve injury by locally translating Anxa2 in pseudopods, and undergo an extensive cytoskeleton remodeling. Our results show that, similarly to neurons, Schwann cells take advantage of local protein synthesis to change shape and move toward damaged axonal terminals to facilitate axonal regeneration.

Development of Oxidized Polyvinyl Alcohol-Based Nerve Conduits Coupled with the Ciliary Neurotrophic Factor

“…Neat and oxidized PVA cytotoxic effects were evaluated on a) the human neuroblastoma cell line SH-SY5Y (ATCC, Manassas, VA, USA) and b) primary cultures of Schwann cells isolated from a rat sciatic nerve according to a published protocol [27,28]. SH-SY5Y cells were cultured in 25 cm 2 -flasks (Corning, NY, USA) using DMEM/F-12 (Dulbecco’s Modified Eagle Medium/Nutrient Mixture F-12) supplemented with 15% fetal bovine serum (FBS) and 1% penicillin (10,000 U/mL)/streptomycin (10 mg/mL) solution.…”

Repair Schwann cell update: Adaptive reprogramming, EMT, and stemness in regenerating nerves

“…There is evidence that purines, which have a role in many other injury responses, play a part through activation of Schwann cell protein kinase C or ERK1/2 (Negro et al, ; Xu et al, ). Neurone‐derived hydrogen peroxide has also been implicated in early Schwann cell activation involving Annexin proteins (Duregotti et al, ; Negro et al, ), and induction of injury‐related cytoskeletal changes (Gomez‐Sanchez et al, ; Reynolds & Wolf, ; Son, Trachtenberg, & Thompson, ).…”

Signals Orchestrating Peripheral Nerve Repair

“…Releasing brakes (for example, by inhibition of Rho GTPases by oxidation) is among the mechanisms that promote axonal re-growth [130]. H 2 O 2 is able to rewire in primary SC the expression of several RNAs at both transcriptional and translational levels, among them genes involved in cytoskeleton remodeling and cell migration, with the Annexin (Anxa) proteins being the most represented family [131]. Both Anxa2 transcripts and proteins accumulate at the tip of long processes that SC extend upon H 2 O 2 exposure and, interestingly, SC reply to this signal by locally translating Anxa2 in pseudopods, and by undergoing extensive cytoskeleton remodeling [131].…”

“…H 2 O 2 is able to rewire in primary SC the expression of several RNAs at both transcriptional and translational levels, among them genes involved in cytoskeleton remodeling and cell migration, with the Annexin (Anxa) proteins being the most represented family [131]. Both Anxa2 transcripts and proteins accumulate at the tip of long processes that SC extend upon H 2 O 2 exposure and, interestingly, SC reply to this signal by locally translating Anxa2 in pseudopods, and by undergoing extensive cytoskeleton remodeling [131]. Hence, similar to neurons, SC take advantage of local protein synthesis to change shape and move toward damaged axon terminals to facilitate axonal regeneration in an H 2 O 2 -dependent manner.…”