AUTHOR=Hoffner O’Connor Michelle , Berglind Ana , Kennedy Ng Meaghan M. , Keith Benjamin P. , Lynch Zachary J. , Schaner Matthew R. , Steinbach Erin C. , Herzog Jeremy , Trad Omar K. , Jeck William R. , Arthur Janelle C. , Simon Jeremy M. , Sartor R. Balfour , Furey Terrence S. , Sheikh Shehzad Z. TITLE=BET Protein Inhibition Regulates Macrophage Chromatin Accessibility and Microbiota-Dependent Colitis JOURNAL=Frontiers in Immunology VOLUME=13 YEAR=2022 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2022.856966 DOI=10.3389/fimmu.2022.856966 ISSN=1664-3224 ABSTRACT=Introduction

In colitis, macrophage functionality is altered compared to normal homeostatic conditions. Loss of IL-10 signaling results in an inappropriate chronic inflammatory response to bacterial stimulation. It remains unknown if inhibition of bromodomain and extra-terminal domain (BET) proteins alters usage of DNA regulatory elements responsible for driving inflammatory gene expression. We determined if the BET inhibitor, (+)-JQ1, could suppress inflammatory activation of macrophages in Il10-/- mice.

Methods

We performed ATAC-seq and RNA-seq on Il10-/- bone marrow-derived macrophages (BMDMs) cultured in the presence and absence of lipopolysaccharide (LPS) with and without treatment with (+)-JQ1 and evaluated changes in chromatin accessibility and gene expression. Germ-free Il10-/- mice were treated with (+)-JQ1, colonized with fecal slurries and underwent histological and molecular evaluation 14-days post colonization.

Results

Treatment with (+)-JQ1 suppressed LPS-induced changes in chromatin at distal regulatory elements associated with inflammatory genes, particularly in regions that contain motifs for AP-1 and IRF transcription factors. This resulted in attenuation of inflammatory gene expression. Treatment with (+)-JQ1 in vivo resulted in a mild reduction in colitis severity as compared with vehicle-treated mice.

Conclusion

We identified the mechanism of action associated with a new class of compounds that may mitigate aberrant macrophage responses to bacteria in colitis.