Nucleosome loss facilitates the chemotactic response of macrophages

Background High mobility group box 1 ( HMGB 1) 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 HMGB 1 is secreted from inflammatory cells, it relocates to the cytoplasm, which partially or totally depletes cell nuclei of HMGB 1. We previously showed that cells lacking HMGB 1 contain 20% fewer nucleosomes and 30% more RNA transcripts levels genome‐wide. Objective We hypothesized that the depletion of nuclear HMGB 1 plays a role in inflammation that can enhance or complement the role of extracellular HMGB 1. Methods We analysed the transcriptional profile of wild‐type and H mgb1 −/− mouse embryonic fibroblasts ( MEF s) as a proxy for cells that have lost HMGB 1 from their nuclei. We explored the transcriptome of wild‐type and H mgb1 −/− 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 HMGB 1 were quantified. Results We found that H mgb1 −/− MEF s show a transcriptional profile associated with stress and inflammation responses. Moreover, wild‐type macrophages that have secreted HMGB 1 because of LPS / IFN ‐γ exposure rapidly reduce their histone content as much as cells that genetically lack HMGB 1. Importantly, unstimulated H mgb1 −/− 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. HMGB 1's dual roles in the nucleus and in the extracellular space appear to be complementary.