| First Author | Hoffner O'Connor M | Year | 2022 |
| Journal | Front Immunol | Volume | 13 |
| Pages | 856966 | PubMed ID | 35401533 |
| Mgi Jnum | J:324000 | Mgi Id | MGI:7261827 |
| Doi | 10.3389/fimmu.2022.856966 | Citation | Hoffner O'Connor M, et al. (2022) BET Protein Inhibition Regulates Macrophage Chromatin Accessibility and Microbiota-Dependent Colitis. Front Immunol 13:856966 |
| abstractText | 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. |
