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A reversible KO model reveals therapeutic potentials of defective Tregs

ABSTRACT: To characterize Brg1-reexpressed Tregs, we treated 3-wks-old rKO1 mice with the low dose of TAM and compared gene expression patterns in Brg1-deleted (GFP+) vs. Brg1-reexpressed (GFP- ) Treg subsets isolated 7 days after TAM. Brg1-deletion in the mosaic females and Brg1-reexpression in rKO1 mice on Day 7 after TAM treatment affected 618 and 1352 genes, respectively, with only 241 genes shared, suggesting divergent roles of Brg1 under the physiological vs. inflammatory conditions. These genes can be divided into two categories: the “naïve genes” that are predominantly expressed in naïve Tregs and “activation/effector function genes” preferentially expressed in activated/effector Tregs. Our data collectively suggest that Brg1 reexpression acted (partly) in conjunction with inflammatory cytokines to convert Brg1-deleted Tregs into hyperactivated Tregs endowed with potent suppressive activity

ORGANISM(S): Mus musculus

PROVIDER: GSE132562 | GEO | 2020/02/21

REPOSITORIES: GEO

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Project description:To compare tumor associated macrophage (TAM) from naïve and sepsis surviving mice we have employed Agilent microarrays slides with almost 60,000 genes (39,430 mRNA and 16,251 long non coding RNAs). Other experiments we conducted demonstrated TAM accumulation was increased in post-sepsis subjects. For this reason, we asked if TAM from post-sepsis mice could also exhibit a different gene expression profile. Sepsis was induced by cecal and ligation puncture. Naïve mice were used as control group. All animals were treated with ertapenem (20 mg/kg, i.p., 6 hours after surgery, and then each 12 hours for 3 days). B16-F10 melanoma (30,000 cells) were injected subcutaneously at day 14 after sepsis induction. Fourteen days after tumor inoculation, animals were killed and tumors were harvested and digested (collagenase and DNAse). TAM was isolated by a Percoll gradient (70/30) followed by a 1-hour adhesion protocol, reaching a purity of ~75%. For comparative reasons, we assessed TAM from post-sepsis (n = 4), TAM from naïve mice (n = 4), bone marrow derived macrophage from naïve (n = 4) and from post-sepsis (n = 4), M1-polarized macrophage (n = 4) and M2-polarized macrophage (n = 4). We found only minor gene expression differences between TAM from naïve and from post-sepsis mice (61 genes were up-regulated and 98 genes were down-regulated, fold-change > 0.58 or < -0.58, and p < 0.01). We found genes related to leukocyte activation were down-regulated in TAM from post-sepsis mice (e.g. Ccr7, Cd86, H2-Ab1), as well as genes related to antigen processing and presentation of peptide or polysaccharide antigen via MHC class II (H2-DMb1, Cd74, H2-Eb1, H2-Ob). A gene related to M2 polarization was up-regulated (Marco). Also, we found a down-regulation of Nfkbid in post-sepsis-derived TAM. This led us to hypothesize TAM from post-sepsis mice exhibit a more M2-like phenotype, which may in part contribute to post-sepsis tumor expansion. Three independent experiments were conducted for TAM obtaining, each experiment using n = 4 for naïve and n = 4 for post-sepsis. We selected the 4 best within a group of 12 samples, following A260/280 and A260/230 ratios. For bone marrow derived macrophage from naïve and from post-sepsis, and for M1 and M2-polarized macrophage, we conducted two independent experiments using n = 3 per group. The best 4 samples in each group was selected to microarray processing and analysis.

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A reversible KO model reveals therapeutic potentials of defective Tregs

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