Nucleosome loss facilitates the chemotactic response of macrophages

I. De Toma, G. Rossetti, S. Zambrano, M. E. Bianchi, A. Agresti

Research output: Contribution to journalArticlepeer-review

Abstract

Background: High mobility group box 1 (HMGB1) is a small nuclear protein with two functions. In the nucleus, it helps to wrap DNA around nucleosomes. When secreted, it recruits inflammatory cells and induces cytokine production. Before HMGB1 is secreted from inflammatory cells, it relocates to the cytoplasm, which partially or totally depletes cell nuclei of HMGB1. We previously showed that cells lacking HMGB1 contain 20% fewer nucleosomes and 30% more RNA transcripts levels genome-wide. Objective: We hypothesized that the depletion of nuclear HMGB1 plays a role in inflammation that can enhance or complement the role of extracellular HMGB1. Methods: We analysed the transcriptional profile of wild-type and Hmgb1-/- mouse embryonic fibroblasts (MEFs) as a proxy for cells that have lost HMGB1 from their nuclei. We explored the transcriptome of wild-type and Hmgb1-/- macrophages differentiated in the presence of granulocyte-macrophage colony-stimulating factor, before and after exposure to LPS/IFN-γ. In the same cells, histones and nuclear HMGB1 were quantified. Results: We found that Hmgb1-/- MEFs show a transcriptional profile associated with stress and inflammation responses. Moreover, wild-type macrophages that have secreted HMGB1 because of LPS/IFN-γ exposure rapidly reduce their histone content as much as cells that genetically lack HMGB1. Importantly, unstimulated Hmgb1-/- macrophages activate transcriptional pathways associated with cell migration and chemotaxis. Conclusions: We suggest that nucleosome loss is an early event that facilitates transcriptional responses of macrophages to inflammation, particularly chemotaxis. HMGB1's dual roles in the nucleus and in the extracellular space appear to be complementary.

Original languageEnglish
Pages (from-to)454-469
Number of pages16
JournalJournal of Internal Medicine
Volume276
Issue number5
DOIs
Publication statusPublished - Nov 1 2014

Keywords

  • Epigenetics
  • HMGB1
  • Inflammation
  • Monocytes
  • Nucleosomes
  • Transcription

ASJC Scopus subject areas

  • Internal Medicine
  • Medicine(all)

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