Janus Kinase Inhibitor Brepocitinib Rescues Myelin Phagocytosis Under Inflammatory Conditions: In Vitro Evidence from Microglia and Macrophage Cell Lines

Lorenzo Romero-Ramirez*, Concepcion Garcia-Rama, Jorg Mey

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Central nervous system (CNS) injuries induce cell death and consequently the release of myelin and other cellular debris. Microglia as well as hematogenous macrophages actively collaborate to phagocyte them and undergo their degradation. However, myelin accumulation persists in the lesion site long after the injury with detrimental effects on axonal regeneration. This might be due to the presence of inhibitors of phagocytosis in the injury site. As we recently published that some proinflammatory stimuli, like interferon-γ (IFNγ) and lipopolysaccharide (LPS), inhibit myelin phagocytosis in macrophages, we have now studied the signaling pathways involved. A phagocytosis assay in Raw264.7 macrophages and N13 microglia cell lines with labeled myelin was developed with the pHrodo reagent that emits fluorescence in acidic cellular compartments (e.g.lysosomes). Pharmacological inhibition of Janus kinases (Jak) with Brepocitinib restored myelin phagocytosis and rescued the expression of genes related to phagocytosis, like triggering receptor expressed on myeloid cells 2 (TREM2), induced by IFNγ or LPS. In addition, while pharmacological inhibition of the signal transducer and activator of transcription 3 (STAT3) rescued myelin phagocytosis and the expression of phagocytosis related genes in the presence of LPS, it did not have any effect on IFNγ-treated cells. Our results show that Jak pathways participate in the inhibition of myelin phagocytosis by IFNγ and LPS. They also indicate that the resolution of inflammation is important for the clearance of cellular debris by macrophages and subsequent regenerative processes.

Original languageEnglish
Pages (from-to)6423-6434
Number of pages12
JournalMolecular Neurobiology
Volume61
Issue number9
Early online date1 Feb 2024
DOIs
Publication statusPublished - Sept 2024

Keywords

  • Brepocitinib
  • Janus kinases
  • IFN gamma
  • LPS
  • Macrophages
  • Myelin phagocytosis
  • TYROSINE PHOSPHORYLATION
  • APOPTOTIC NEUTROPHILS
  • ACTIVATION
  • STAT3
  • EXPRESSION

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