Increased TNFR1 expression and signaling in injured peripheral nerves of mice with reduced BACE1 activity

Lijuan Liu, John A. Fissel, Aniqa Tasnim, Jasenka Borzan, Anne Gocke, Peter A. Calabresi, Mohamed H. Farah

Research output: Contribution to journalArticlepeer-review

Abstract

Hematogenous macrophages remove myelin debris from injured peripheral nerves to provide a micro-environment conducive to axonal regeneration. Previously, we observed that injured peripheral nerves from Beta-site APP Cleaving Enzyme 1 (BACE1) knockout (KO) mice displayed earlier influx of and enhanced phagocytosis by macrophages when compared to wild-type (WT) mice. These observations suggest that BACE1 might regulate macrophage influx into distal stumps of injured nerves. To determine through which pathway BACE1 influences macrophage influx, we used a mouse inflammation antibody array to assay the expression of inflammation-related proteins in injured nerves of BACE1 KO and WT mice. The most significant change was in expression of tumor necrosis factor receptor 1 (TNFR1) in the distal stump of injured BACE1 KO nerves. Western blotting of protein extracts confirmed increased expression of TNFR1 and its downstream transcriptional factor NFκB in the BACE1 KO distal stumps. Additionally, treatment of WT mice with a BACE1 inhibitor resulted in increased TNFR1 expression and signaling in the distal stump of injured nerves. Exogenous TNFα increased nuclear translocation of p65 NFκB in BACE1 KO tissue and cultured fibroblasts compared with control WT. BACE1 regulates TNFR1 expression at the level of gene expression and not through proteolytic processing. The accelerated macrophage influx in injured nerves of BACE1 KO mice correlates with increased expression and signaling via TNFR1, indicating a link between BACE1 activity and TNFR1 expression/signaling that might contribute to repair of the injured nervous system.

Original languageEnglish (US)
Pages (from-to)21-27
Number of pages7
JournalNeurobiology of Disease
Volume93
DOIs
StatePublished - Sep 1 2016

Keywords

  • Macrophages in the PNS
  • Nervous system injury
  • Neuroinflammation

ASJC Scopus subject areas

  • Neurology

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