The p-rpS6-zone delineates wounding responses and the healing process.

The spatial boundaries of tissue response to wounding are unknown. Here, we show that in mammals, the ribosomal protein S6 (rpS6) is phosphorylated in response to skin injury, forming a zone of activation surrounding the region of the initial insult. This p-rpS6-zone forms within minutes after wounding and is present until healing is complete. The zone is a robust marker of healing as it encapsulates features of the healing process, including proliferation, growth, cellular senescence, and angiogenesis. A mouse model that is unable to phosphorylate rpS6 shows an initial acceleration of wound closure, but results in impaired healing, identifying p-rpS6 as a modulator but not a driver of healing. Finally, the p-rpS6-zone accurately reports on the status of dermal vasculature and the effectiveness of healing, visually dividing an otherwise homogeneous tissue into regions with distinct properties.

Extracellular vesicles and their role in peripheral nerve regeneration.

Peripheral nerve injuries often result in sensory and motor dysfunction in respective parts of the body. Regeneration after peripheral nerve injuries is a complex process including the differentiation of Schwann cells, recruiting of macrophages, blood vessel growth and axonal regrowth. Extracellular vesicles (EVs) are considered to play a pivotal role in intercellular communication and transfer of biological information. Specifically, their bioactivity and ability to deliver cargos of various types of nucleic acids and proteins have made them a potential vehicle for neurotherapeutics. However, production, characterization, dosage and targeted delivery of EVs still pose challenges for the clinical translation of EV therapeutics. This review summarizes the current knowledge of EVs in the context of the healthy and injured peripheral nerve and addresses novel concepts for modification of EVs as therapeutic agents for peripheral nerve regeneration.

Context-Dependent IL-1 mRNA-Destabilization by TTP Prevents Dysregulation of Immune Homeostasis Under Steady State Conditions.

The bioavailability of the major pro-inflammatory cytokines IL-1α and IL-1ß is tightly controlled by transcription and post-translational processing to prevent hyperinflammation. The role of mRNA decay in maintenance of physiological IL-1 amounts remained unknown. Here we show that the down-regulation of Il1a and Il1b mRNA by the mRNA-destabilizing protein TTP (gene Zfp36) is required for immune homeostasis. The TTP deficiency syndrome, a multi organ inflammation in TTP-/- mice, was significantly ameliorated upon deletion of the IL-1 receptor. Il1a and Il1b played non-redundant roles in triggering the pathological IL-1 signaling in TTP-/- mice. Accordingly, tissues from TTP-/- animals contained increased amounts of Il1b mRNA. Unexpectedly, TTP destabilized Il1b mRNA in cell type-specific ways as evident from RNA-Seq and mRNA stability assays. These results demonstrate that TTP-driven mRNA destabilization depends on the cellular context. Moreover, such context-defined mRNA decay is essential for keeping steady state IL-1 levels in the physiological range.