Role of SMARCAD-1 protein in macrophage function and microbiota-host interactions

• Grant number: 20/00311-0
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• Effective date (Start): October 01, 2020
• Effective date (End): September 30, 2024
• Field of knowledge: Biological Sciences - Immunology - Cellular Immunology
• Principal Investigator: Marco Aurélio Ramirez Vinolo
• Grantee: Helder Carvalho de Assis
• Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil
• Associated research grant: 18/15313-8 - Investigation of the molecular mechanisms involved in the interaction between microbiota-derived metabolites and host cells during inflammation, AP.JP2

Abstract

Interactions between microbiota and the host immune system are essential for homeostasis maintenance. Previous work by the group showed that the deletion of a chromatin remodeling factor called Smarcad-1 in intestinal epithelial cells resulted in a change in this interaction, establishment of different composition microbiota, and resistance to induction of colitis by DSS relative to control mice expressing Smarcad-1. Considering the relevance of epigenetic mechanisms in macrophage function and that macrophages are essential cells in the microbiota-host interaction, we aim to analyze the impact of Smarcad-1 on gene regulation and how these cells behave under homeostasis and intestinal inflammation conditions. For such purpose, the tissue-specific deletion of factor Smarcad-1 will be made in macrophages using the Cre-Loxp system. LysMCre mice will be cross-bred with mice that have the Smarcad-1 exons-11-15 floxed and mice resulting from those crosses (LysMCre + Smarcad-1 and LysMCre-Smarcad-1) will be used for in vitro and in vivo analysis. Through in vitro assays we will evaluate if Smarcad-1 deficiency implies changes in the polarization profiles (M1 and M2) and activity (phagocytosis and efferocytosis) of Bone Marrow-Derived Macrophages (BMDM), besides investigating the transcriptome and modifications of histones of these macrophages. We will also investigate the impact of Smarcad-1 on microbiota-host interactions in vivo. We will analyze in LysMCre + Smarcad-1 and LysMCre-Smarcad-1 mice intestinal microbiota composition, intestinal production of Short Chain Fatty Acids (SCFAs), intestinal mucosal leukocyte population and immunological activity such as antimicrobial peptide production, mucus and cytokines. Finally, it will be investigated how Smarcad-1 deficiency affects the inflammatory response in vivo through a model of acute DSS-induced intestinal inflammation. Our hypothesis is that this protein is relevant in regulating gene expression in macrophages and, consequently, in its functionality. (AU)