Angiopoietin-like 4 Mediates Colonic Inflammation by Regulating Chemokine Transcript Stability via Tristetraprolin

Abstract

Many gastrointestinal diseases exhibit a protracted and aggravated inflammatory response that can lead to hypercytokinaemia, culminating in extensive tissue damage. Recently, angiopoietin-like 4 (ANGPTL4) has been implicated in many inflammation-associated diseases. However, how ANGPTL4 regulates colonic inflammation remains unclear. Herein, we show that ANGPTL4 deficiency in mice (ANGPTL4−/−) exacerbated colonic inflammation induced by dextran sulfate sodium (DSS) or stearic acid. Microbiota was similar between the two genotypes prior DSS challenge. A microarray gene expression profile of the colon from DSS-treated ANGPTL4−/− mice was enriched for genes involved in leukocyte migration and infiltration, and showed a close association to inflamed ulcerative colitis (UC), whereas the profile from ANGPTL4+/+ littermates resembled that of non-inflamed UC biopsies. Bone marrow transplantation demonstrates the intrinsic role of colonic ANGPTL4 in regulating leukocyte infiltration during DSS-induced inflammation. Using immortalized human colon epithelial cells, we revealed that the ANGPTL4-mediated upregulation of tristetraprolin expression operates through CREB and NF-κB transcription factors, which in turn, regulates the stability of chemokines. Together, our findings suggest that ANGPTL4 protects against acute colonic inflammation and that its absence exacerbates the severity of inflammation. Our findings emphasize the importance of ANGPTL4 as a novel target for therapy in regulating and attenuating inflammation.

Gene Expression Comparison Between the Lymph Node-Positive and Negative Reveals a Peculiar Immune-microenvironment Signature and a Theranostic Role for WNT Targeting in Pancreatic Ductal Adenocarcinoma: A Pilot Study

“…is also involved in the regulation of immune homeostasis, modulating inflammatory T-cells response and cytokines expression such as IL10 and IL1. These compelling evidences corroborated our in-silico data (Figure 4b) being also reported as immune activation repressor [49]. Remarkably, our experimental evidences parallel previous report about ANGPLT4, as an up-stream regulator of WNTpathway and an agonist of PKC, the main XAV-939 target [50].…”

Meningitic Escherichia coli Induction of ANGPTL4 in Brain Microvascular Endothelial Cells Contributes to Blood–Brain Barrier Disruption via ARHGAP5/RhoA/MYL5 Signaling Cascade

“…A study showed that nANGPTL4 is an orphan ligand that mainly controls lipid metabolism and cANGPTL4 binds-e.g., β-integrins, VE-cadherin, and claudin-5-to induce vascular leakage and tumor progression [19]. An increasing number of studies have indicated the possible involvement of ANGPTL4 in the development of cardiovascular diseases [20][21][22], inflammatory diseases [23][24][25][26], cancers [27][28][29], etc. However, there are still no reports on the role of ANGPTL4 in bacterial meningitis.…”

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“…Angptl4 protected against acute colonic in ammation and that its absence worsened the severity of in ammation [32]. As the critical enzyme in FA metabolism, SCD is responsible for the conversion of saturated FAs to unsaturated FAs, and oleic acid is one of the major products [33]. Researchers found that gut-speci c SCD-1 activity is necessary to control intestinal epithelial in ammation and synthetize oleate, and that dietary oleic acid provides protection against intestinal in ammation in vivo [34].…”