M2 macrophage-derived cathepsin S promotes peripheral nerve regeneration via fibroblast-Schwann cell-signaling relay.

Publisher: BioMed Central Country of Publication: England NLM ID: 101222974 Publication Model: Electronic Cited Medium: Internet ISSN: 1742-2094 (Electronic) Linking ISSN: 17422094 NLM ISO Abbreviation: J Neuroinflammation Subsets: MEDLINE

Original Publication: [London] : BioMed Central, c2004-

Axons*/pathology ; Peripheral Nerve Injuries*/metabolism; Animals ; Humans ; Rats ; Cathepsins/metabolism ; Cathepsins/pharmacology ; Ephrin-B2/metabolism ; Ephrin-B2/pharmacology ; Fibroblasts/metabolism ; Macrophages/metabolism ; Nerve Regeneration ; Peripheral Nerves/pathology ; Rats, Sprague-Dawley ; Schwann Cells/metabolism

Background: Although peripheral nerves have an intrinsic self-repair capacity following damage, functional recovery is limited in patients. It is a well-established fact that macrophages accumulate at the site of injury. Numerous studies indicate that the phenotypic shift from M1 macrophage to M2 macrophage plays a crucial role in the process of axon regeneration. This polarity change is observed exclusively in peripheral macrophages but not in microglia and CNS macrophages. However, the molecular basis of axonal regeneration by M2 macrophage is not yet fully understood. Herein, we aimed to identify the M2 macrophage-derived axon regeneration factor.
Methods: We established a peripheral nerve injury model by transection of the inferior alveolar nerve (IANX) in Sprague-Dawley rats. Transcriptome analysis was performed on the injured nerve. Recovery from sensory deficits in the mandibular region and histological reconnection of IAN after IANX were assessed in rats with macrophage depletion by clodronate. We investigated the effects of adoptive transfer of M2 macrophages or M2-derived cathepsin S (CTSS) on the sensory deficit. CTSS initiating signaling was explored by western blot analysis in IANX rats and immunohistochemistry in co-culture of primary fibroblasts and Schwann cells (SCs).
Results: Transcriptome analysis revealed that CTSS, a macrophage-selective lysosomal protease, was upregulated in the IAN after its injury. Spontaneous but partial recovery from a sensory deficit in the mandibular region after IANX was abrogated by macrophage ablation at the injured site. In addition, a robust induction of c-Jun, a marker of the repair-supportive phenotype of SCs, after IANX was abolished by macrophage ablation. As in transcriptome analysis, CTSS was upregulated at the injured IAN than in the intact IAN. Endogenous recovery from hypoesthesia was facilitated by supplementation of CTSS but delayed by pharmacological inhibition or genetic silencing of CTSS at the injured site. Adoptive transfer of M2-polarized macrophages at this site facilitated sensory recovery dependent on CTSS in macrophages. Post-IANX, CTSS caused the cleavage of Ephrin-B2 in fibroblasts, which, in turn, bound EphB2 in SCs. CTSS-induced Ephrin-B2 cleavage was also observed in human sensory nerves. Inhibition of CTSS-induced Ephrin-B2 signaling suppressed c-Jun induction in SCs and sensory recovery.
Conclusions: These results suggest that M2 macrophage-derived CTSS contributes to axon regeneration by activating SCs via Ephrin-B2 shedding from fibroblasts.
(© 2023. The Author(s).)

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Uemura Fund (UEMURA-2023-2) School of Dentistry, Nihon University; Sato Fund School of Dentistry, Nihon University; 23K09405 Japan Society for the Promotion of Science; 20K18678 Japan Society for the Promotion of Science; 22K10158 Japan Society for the Promotion of Science; 19K10049 Japan Society for the Promotion of Science; Chairman of the Board of Trustees Grant (2020-2021) Nihon University

Keywords: Axon regeneration; Cathepsin S; Ephrin-B2; Gene expression; Macrophage; Peripheral nerve injury; Schwann cells

EC 3.4.- (Cathepsins)
0 (Ephrin-B2)
EC 3.4.22.27 (cathepsin S)

Date Created: 20231110 Date Completed: 20231115 Latest Revision: 20231115

20250114

PMC10636844

10.1186/s12974-023-02943-2

37946211