Toll-Like Receptor 4 Promotes Autonomic Dysfunction, Inflammation and Microglia Activation in the Hypothalamic Paraventricular Nucleus: Role of Endoplasmic Reticulum Stress
| Autor: | Rahul B. Dange, Gustavo S. Masson, Lisete Compagno Michelini, Pedro Paulo Silva-Soares, Joseph Francis, Anand R. Nair |
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| Rok vydání: | 2015 |
| Předmět: |
Lipopolysaccharides
medicine.medical_specialty medicine.medical_treatment Gene Expression lcsh:Medicine Baroreflex Norepinephrine Internal medicine medicine Animals lcsh:Science Receptor Heat-Shock Proteins Inflammation Neurons Multidisciplinary biology Tumor Necrosis Factor-alpha Endoplasmic reticulum lcsh:R Endoplasmic Reticulum Stress Rats Toll-Like Receptor 4 Disease Models Animal Cytokine Endocrinology ESTRESSE TLR4 biology.protein Unfolded protein response lcsh:Q lipids (amino acids peptides and proteins) Tumor necrosis factor alpha Microglia NeuN Paraventricular Hypothalamic Nucleus Signal Transduction Research Article |
| Zdroj: | PLoS ONE, Vol 10, Iss 3, p e0122850 (2015) Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP PLoS ONE |
| ISSN: | 1932-6203 |
| DOI: | 10.1371/journal.pone.0122850 |
| Popis: | Background & Purpose Toll-like receptor 4 (TLR4) signaling induces tissue pro-inflammatory cytokine release and endoplasmic reticulum (ER) stress. We examined the role of TLR4 in autonomic dysfunction and the contribution of ER stress. Experimental approach Our study included animals divided in 6 experimental groups: rats treated with saline (i.v., 0.9%), LPS (i.v., 10mg/kg), VIPER (i.v., 0.1 mg/kg), or 4-PBA (i.p., 10 mg/kg). Two other groups were pretreated either with VIPER (TLR4 viral inhibitory peptide) LPS + VIPER (i.v., 0.1 mg/kg) or 4-Phenyl butyric acid (4-PBA) LPS + PBA (i.p., 10 mg/kg). Arterial pressure (AP) and heart rate (HR) were measured in conscious Sprague-Dawley rats. AP, HR variability, as well as baroreflex sensitivity (BrS), was determined after LPS or saline treatment for 2 hours. Immunofluorescence staining for NeuN, Ib1a, TLR4 and GRP78 in the hypothalamic paraventricular nucleus (PVN) was performed. TNF-α, TLR4 and GRP78 protein expression in the PVN were evaluated by western blot. Plasma norepinephrine levels were determined by ELISA. Key Results Acute LPS treatment increased HR and plasma norepinephrine concentration. It also decreased HR variability and high frequency (HF) components of HR variability, as well BrS. Acute LPS treatment increased TLR4 and TNF-α protein expression in the PVN. These hemodynamic and molecular effects were partially abrogated with TLR4 blocker or ER stress inhibitor pretreatment. In addition, immunofluorescence study showed that TLR4 is co-localized with GRP78in the neurons. Further inhibition of TLR4 or ER stress was able to attenuate the LPS-induced microglia activation. Conclusions & Implications TLR4 signaling promotes autonomic dysfunction, inflammation and microglia activation, through neuronal ER stress, in the PVN. |
| Databáze: | OpenAIRE |
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