Telmisartan Protects a Microglia Cell Line from LPS Injury Beyond AT1 Receptor Blockade or PPARγ Activation

Abstract

The Angiotensin II Receptor Blocker (ARB) Telmisartan reduces inflammation through Angiotensin II AT1 receptor blockade and peroxisome proliferator-activated receptor gamma (PPARγ) activation. However, in a mouse microglia-like BV2 cell line, imitating primary microglia responses with high fidelity and devoid of AT1 receptor gene expression or PPARγ activation, Telmisartan reduced gene expression of pro-injury factors, enhanced that of anti-inflammatory genes, and prevented LPS-induced increase in inflammatory markers. Using global gene expression profiling and pathways analysis, we revealed that Telmisartan normalized the expression of hundreds of genes upregulated by LPS and linked with inflammation, apoptosis and neurodegenerative disorders, while downregulating the expression of genes associated with oncological, neurodegenerative and viral diseases. The PPARγ full agonist Pioglitazone had no neuroprotective effects. Surprisingly, the PPARγ antagonists GW9662 and T0070907 were neuroprotective and enhanced Telmisartan effects. GW9226 alone significantly reduced LPS toxic effects and enhanced Telmisartan neuroprotection, including downregulation of pro-inflammatory TLR2 gene expression. Telmisartan and GW9662 effects on LPS injury negatively correlated with pro-inflammatory factors and upstream regulators, including TLR2, and positively with known neuroprotective factors and upstream regulators. Gene Set Enrichment Analysis (GSEA) of the Telmisartan and GW9662 data revealed negative correlations with sets of genes associated with neurodegenerative and metabolic disorders and toxic treatments in cultured systems, while demonstrating positive correlations with gene sets associated with neuroprotection and kinase inhibition. Our results strongly suggest that novel neuroprotective effects of Telmisartan and GW9662, beyond AT1 receptor blockade or PPARγ activation, include downregulation of the TLR2 signaling pathway, findings that may have translational relevance.

Asperosaponin VI ameliorates the CMS-induced depressive-like behaviors by inducing a neuroprotective microglial phenotype in hippocampus via PPAR-γ pathway

“…The purified microglial cells were cultured at 37 °C in DMED-F12 medium (Gibco, CA, USA) containing 10% fetal bovine serum (Gibco, CA, USA). Seven days later, microglia were pre-treated with 40 μM ASA VI (Alfabiotech, Chengdu, China) or 10 μM GW9662 (Sigma-Aldrich, MO, USA) [ 24 ]. After 30 min, microglia were treated for 24 h with either 50 ng/mL lipopolysaccharide (LPS; Sigma-Aldrich, MO, USA) or phosphate-buffered saline (PBS; BOSTER, Wuhan, China) (control).…”

Telmisartan Inhibits TNFα-Induced Leukocyte Adhesion by Blocking ICAM-1 Expression in Astroglial Cells but Not in Endothelial Cells

“…Telmisartan is an angiotensin-II type 1 receptor blocker and peroxisome proliferator-activated gamma (PPARγ) agonist used to treat hypertension ( Benson et al ., 2004 ). PPAR activation suppresses inflammatory responses in neurons, endothelial cells, astrocytes, and microglial cells and promotes amyloid β clearance ( Camacho et al ., 2004 ; Elkahloun et al ., 2018 ). Telmisartan had protective effects on memory impairment, glial inflammation, and amyloid burden in a transgenic mouse model of AD ( Tsukuda et al ., 2009 ; Torika et al ., 2017 ).…”

Microglial TREM2 Mitigates Inflammatory Responses and Neuronal Apoptosis in Angiotensin II-Induced Hypertension in Middle-Aged Mice

“…To test the hypothesis, we incubated an immortalized mouse microglialike BV2 cell line in an LPS-containing cell culture medium to mimic a neuroinflammatory environment (Lund et al, 2006). We found that the BV2 microglial cells mimicked primary microglia responses with high fidelity (Elkahloun et al, 2019) and were more tolerable for manipulating TREM2 overexpression. Because angiotensin II induces microglial activation through AT1R interacts with TLR4, and BV2 cells are devoid of AT1 receptor gene expression (Xu et al, 2015), BV2 cells are especially suitable for the present study to elucidate the mechanism focusing on TREM2-mediated microglial anti-inflammatory responses via LPS-ignited TLR4 pathway (Srinivasan et al, 2016;Zheng et al, 2016).…”