Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Journal stats
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • ASCI Milestone Awards
    • Video Abstracts
    • Conversations with Giants in Medicine
  • Reviews
    • View all reviews ...
    • The cGAS-STING pathway: DNA sensing in health and disease (Jun 2026)
    • Neurodegeneration (Mar 2026)
    • Clinical innovation and scientific progress in GLP-1 medicine (Nov 2025)
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • ASCI Milestone Awards
  • Video Abstracts
  • Conversations with Giants in Medicine
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Journal stats
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Peroxisomal integrity in demyelination-associated microglia enables cellular debris clearance and myelin renewal in mice
Joseph A. Barnes-Vélez, Xiaohong Zhang, Yaren L. Peña Señeriz, Kiersten A. Scott, Yinglu Guan, Jian Hu
Joseph A. Barnes-Vélez, Xiaohong Zhang, Yaren L. Peña Señeriz, Kiersten A. Scott, Yinglu Guan, Jian Hu
View: Text | PDF
Research Article Cell biology Inflammation Neuroscience

Peroxisomal integrity in demyelination-associated microglia enables cellular debris clearance and myelin renewal in mice

  • Text
  • PDF
Abstract

Demyelination associated microglia (DMAM) orchestrate the regenerative response to demyelination by clearing myelin debris and promoting oligodendrocyte maturation. Peroxisomal metabolism has emerged as a candidate regulator of DMAMs, though the cell-intrinsic contribution in microglia remains undefined. Here we elucidate the role of peroxisome integrity in DMAMs, using cuprizone-mediated demyelination coupled with conditional KO of peroxisome biogenesis factor 5 (PEX5) in microglia. Absent demyelination, PEX5 conditional KO (PEX5cKO) had minimal impact on homeostatic microglia. However, during cuprizone-induced demyelination, the emergence of DMAMs unmasked a critical requirement for peroxisome integrity. At peak demyelination, PEX5cKO DMAMs exhibited increased lipid droplet burden and reduced lipophagy suggestive of impaired lipid catabolism. Although lipid droplet burden declined during the remyelination phase, PEX5cKO DMAMs accumulated intralysosomal crystals and curvilinear profiles, features that were largely absent in controls. Aberrant lipid processing was accompanied by elevated numbers of lysosomal damage markers and downregulation of the lipid exporter gene Apoe, consistent with defective lipid clearance. Furthermore, the disruptions in PEX5cKO DMAMs were associated with defective myelin debris clearance and impaired remyelination. Together, these findings delineate a stage-specific role for peroxisomes in coordinating lipid processing pathways essential to DMAM function and for enabling a pro-remyelinating environment.

Authors

Joseph A. Barnes-Vélez, Xiaohong Zhang, Yaren L. Peña Señeriz, Kiersten A. Scott, Yinglu Guan, Jian Hu

×

Figure 2

PEX5 loss impairs Apoe expression, aggravating lipid droplet burden and promoting lipid crystal accumulation.

Options: View larger image (or click on image) Download as PowerPoint
PEX5 loss impairs Apoe expression, aggravating lipid droplet burden and ...
(A) Upregulated and downregulated pseudobulk-derived DEGs per immune subcluster. Numbers over bars indicate DEG count >0. (B) Venn diagram triangulating downregulated DEGs detected in DMAM0, DMAM1, and intermediate subclusters. (C) Apoe average expression per immune subcluster split by genotype. (D) Per immune subcluster Apoe-scaled expression across libraries within the CPZ condition. (E) Representative TEM micrographs of phagocytes. Red circles and red arrowheads mark lipid droplets and crystal clefts, respectively. Nonphagocyte area is shaded blue to ease visualization of phagocyte. Scale bar: 2.0 μm. (F) Lipid droplet–positive cells as fraction of total cells imaged. (G) Lipid droplet count per cell assessed. (H) Crystal-positive cells as a fraction of total cells imaged. (I) Crystal cleft count detected per cell. (J) Representative micrographs for BODIPY and lectin staining within the CPZ condition. Nuclei are stained with propidium iodide dye. Scale bar: 10 μm. (K) BODIPY–positive cell count /mm2. (L) BODIPY–positive droplet count per lectin–positive cell. (M) Representative micrographs of dual confocal and reflective microscopy imaging lectin stain and reflective particles (Ref. Par.). Nuclei are stained with propidium iodide. Scale bar: 10 μm. (N) Average area of reflective particle microclusters. (E–N) Representative images were acquired from corpus callosum; cells analyzed and quantitated were imaged from corpus callosum. (F, H, K, and N) Individual data points correspond to biological replicates. (F and H) Square and error bar correspond to mean and SD, respectively. (G, I, and L) Data points represent dataset outliers. Cell number assessed per group are given below each box plot. Statistical analysis for F–I, K, L, and N) involved ANOVA followed by Tukey’s HSD. Adjusted P values are indicated as follows: NS indicates P > 0.05; *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. IRM, interferon-responsive microglia; Pos, positive.

Copyright © 2026 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts