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Edited Filamin A in myeloid cells reduces intestinal inflammation and protects from colitis [scRNA-Seq]

ABSTRACT: Patho-mechanistic origins and disease dynamics of ulcerative colitis are still poorly understood. The actin-crosslinker Filamin A (FLNA) impacts cellular responses through interaction with cytosolic proteins. FLNA exists in two forms that differ only in one amino acid: genome-encoded FLNAQ and FLNAR - generated by post-transcriptional A-to-I editing. FLNA is edited in fibroblasts, smooth muscle- and endothelial cells in the colon. We identified the FLNA editing status as a key determinant of colitis severity. FLNA editing was highest in healthy colons and reduced during acute murine and human colitis. Mice that exclusively express edited FLNAR and do not downregulate editing upon challenge were highly resistant to DSS-induced colitis, whereas fully unedited FLNAQ animals developed severe inflammation. While the genetic induction of FLNA editing influenced transcriptional states of structural cells and the microbiome composition, we found that FLNAR exerts protection specifically via its influence on myeloid cells, which are not edited under physiological conditions. Introducing fixed, fully edited FLNAR did not hamper normal cell migration but reduced macrophage inflammation and rendered neutrophils less prone to NETosis. In conclusion, loss of FLNA editing correlates with colitis severity, and targeted FLNA editing of myeloid cells might serve as a novel therapeutic approach in intestinal inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE296058 | GEO | 2025/05/03

REPOSITORIES: GEO

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Edited Filamin A in myeloid cells reduces intestinal inflammation and protects from colitis [RNA-Seq]

Project description:Patho-mechanistic origins and disease dynamics of ulcerative colitis are still poorly understood. The actin-crosslinker Filamin A (FLNA) impacts cellular responses through interaction with cytosolic proteins. FLNA exists in two forms that differ only in one amino acid: genome-encoded FLNAQ and FLNAR - generated by post-transcriptional A-to-I editing. FLNA is edited in fibroblasts, smooth muscle- and endothelial cells in the colon. We identified the FLNA editing status as a key determinant of colitis severity. FLNA editing was highest in healthy colons and reduced during acute murine and human colitis. Mice that exclusively express edited FLNAR and do not downregulate editing upon challenge were highly resistant to DSS-induced colitis, whereas fully unedited FLNAQ animals developed severe inflammation. While the genetic induction of FLNA editing influenced transcriptional states of structural cells and the microbiome composition, we found that FLNAR exerts protection specifically via its influence on myeloid cells, which are not edited under physiological conditions. Introducing fixed, fully edited FLNAR did not hamper normal cell migration but reduced macrophage inflammation and rendered neutrophils less prone to NETosis. In conclusion, loss of FLNA editing correlates with colitis severity, and targeted FLNA editing of myeloid cells might serve as a novel therapeutic approach in intestinal inflammation.

2025-05-03 | GSE296059 | GEO

Edited Filamin A in myeloid cells reduces intestinal inflammation and protects from colitis

Project description:Patho-mechanistic origins and disease dynamics of ulcerative colitis are still poorly understood. The actin crosslinker Filamin A (FLNA) impacts cellular responses through interaction with numerous, cytosolic proteins. FLNA exists in two forms that differ only in a single amino acid: genome-encoded FLNAQ, and FLNAR - generated by post-transcriptional A-to-I editing. In the intestinal tract, FLNA is edited in fibroblasts, smooth muscle- and endothelial cells and we identified the FLNA editing status as a key determinant of colitis severity. FLNA editing was highest in healthy colons, and reduced during acute murine and human colitis. Mice that exclusively express edited FLNAR and do not downregulate editing upon challenge were highly resistant to DSS-induced colitis, whereas fully unedited FLNAQ animals developed severe inflammation. While the genetic induction of FLNA editing influenced the transcriptional states of intestinal structural cells and microbiome composition, we found that edited FLNAR exerts protection specifically via its influence on myeloid immune cells, which are not edited under physiological conditions. The introduction of a fixed FLNAR editing state, did not hamper normal cell migration but reduced macrophage inflammation and rendered neutrophils less prone to NETosis. We thus conclude that loss of FLNA editing correlates with colitis severity and targeted FLNA editing of myeloid cells might serve as novel therapeutic approach in intestinal inflammation.

2025-04-29 | GSE295910 | GEO

Edited Filamin A in myeloid cells reduces intestinal inflammation and protects from colitis

Project description:Edited Filamin A in myeloid cells reduces intestinal inflammation and protects from colitis

| PRJNA1256771 | ENA

Edited Filamin A in myeloid cells reduces intestinal inflammation and protects from colitis [RNA-Seq]

Project description:Edited Filamin A in myeloid cells reduces intestinal inflammation and protects from colitis [RNA-Seq]

| PRJNA1257421 | ENA

Edited Filamin A in myeloid cells reduces intestinal inflammation and protects from colitis [scRNA-Seq]

Project description:Edited Filamin A in myeloid cells reduces intestinal inflammation and protects from colitis [scRNA-Seq]

| PRJNA1257419 | ENA

The Refilin/Filamin complex regulates filipodia dynamics in oligodendrocyte progenitor cells.

Project description:Actin assembly and dynamics control the shape, motility and functions of diverse cell types. Programme for controlling theses dynamics is hard-coded into actin binding proteins and regulatory proteins. Refilins (RefilinA and RefilinB) are short lived regulatory proteins that interact with the actin-binding protein Filamin to convert it from an actin branching protein into one that bundles. We here show that different mechanisms converge to increase Refilin level in brain NG2+ precursor cells (polydendrocytes) committed to differentiate into the oligodendrocyte lineage. RefilinA is up-regulated through transcriptional activation during commitment into oligodendrocyte progenitor cells (OPC). RefilinB expression relies on PDGF signalling and is further stabilized by a unique auto-inhibitory domain masking the adjacent conserved PEST degradation signal. In NG2+ precursor cells and OPC, the RefilinB/Filamin complex localizes on filipodia protrusions and filipodial processes. Stable ectopic expression of Refilins in cells stimulates membrane remodelling dynamics linked with filipodia growth. These studies extend the function of the Refilin/FLNA complex to cell membrane remodelling linked with reorganization of underlying actin cytoskeleton. We performed whole transcriptomic analysis on the three cell population derived from OPC cells. Three different cultures were done and for each experiment we compared each cell population (NG2+, NG2+/A2B5 and O4) to the other 2 cell populations.

2013-05-01 | E-GEOD-37600 | biostudies-arrayexpress

Genome-Wide Analyses Identify Filamin-A (FLNA) as a Novel Downstream Target for Insulin and IGF1 Action.

Project description:Identification of filamin-A as a target for insulin and IGF1 action. Insulin analogues have been developed to achieve further improvement in the therapy of diabetes. However, modifications introduced into the insulin molecule might enhance their affinity to the insulin-like growth factor-1 receptor (IGF1R). Most tumors, including endometrial cancers, express high levels of IGF1R. The present study was aimed at identifying the entire set of genes that are differentially activated by insulin glargine or detemir, in comparison to regular insulin and IGF1, in Type 1 and Type 2 endometrial cancer cell lines (ECC-1 and USPC-1, respectively). Global gene expression analyses demonstrated a ligand-dependent up-regulated expression of filamin-A (FLNA), a gene that encodes an actin filament cross-linking protein, in both endometrial cancer cell types. Silencing experiments linked to migration assays confirmed the role of FLNA in cell growth and motility. Our data suggest that the activation of distinct sets of genes by glargine may lead to stimulation of specific pathways or, alternatively, may provide additive effects, different from those classically induced by insulin. Given that metastasis is one of the major factors contributing to the aggressiveness of tumors, the identification of FLNA as a downstream target for insulin-like hormones may be of translational relevance in cancer research. Clinical studies in endometrial cancer may add further relevant information regarding the possible differential actions of insulin analogues with respect to native insulin.

2019-01-02 | GSE109022 | GEO

The Refilin/Filamin complex regulates filipodia dynamics in oligodendrocyte progenitor cells.

2013-05-01 | GSE37600 | GEO

Genome-Wide Analyses Identify Filamin-A (FLNA) as a Novel Downstream Target for Insulin and IGF1 Action.

Project description:Genome-Wide Analyses Identify Filamin-A (FLNA) as a Novel Downstream Target for Insulin and IGF1 Action.

| PRJNA429450 | ENA

CRISPR-Cas9 Editing of TLR4 Improves the Outcome of Cardiac Cell Therapy

Project description:We developed and optimized a new electroporation protocol for CRISPR-Cas9 gene editing. This protocol achieved up to 68% success rate, when applied to isolated hMSCs from the heart and epicardial fat of patients with ischemic heart disease. While cell editing resulted lowered TLR4 expression in hMSCs, it did not affect classical markers of hMSCs and proliferation rate. Advanced protein mass spectrometry analysis revealed that edited cells secreted fewer proteins involved in inflammation and in extracellular matrix organization. The immunomodulatory effect of TLR4 editing was apparent in both free and EV-encapsulated proteins. Furthermore, edited cells expressed less NF-ƙB and secreted lower amounts of extracellular vesicles, pro-inflammatory and pro-fibrotic cytokines than unedited hMSCs. Cell therapy with edited and unedited hMSCs improved survival, left ventricular (LV) remodeling, and cardiac function after myocardial infarction (MI) in mice. Postmortem histologic analysis revealed clusters of edited cells that survived in the scar tissue 28 days after MI. Morphometric analysis showed that implantation of edited cells increased the area of myocardial islands in the scar tissue, reduced the occurrence of transmural scar, increased scar thickness, and markedly decreased expansion index, compared with unedited cells or saline.

2023-05-10 | PXD033253 | Pride

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