ave-0991 and Inflammation

Defective absorption of acute allergic airway inflammation is involved in the initiation and development of chronic asthma. After allergen exposure, there is a rapid recruitment of macrophages around the airways, which promote acute inflammatory responses. The Ang-(1-7)/Mas receptor axis reportedly plays protective roles in various tissue inflammation and remodeling processes in vivo. However, the exact role of Mas receptor and their underlying mechanisms during the pathology of acute allergic airway inflammation remains unclear.. We investigated the role of Mas receptor in acute allergic asthma and explored its underlying mechanisms in vitro, aiming to find critical molecules and signal pathways.. Mas receptor expression was assessed in ovalbumin (OVA)-induced acute asthmatic murine model. Then we estimated the anti-inflammatory role of Mas receptor in vivo and explored expressions of several known inflammatory cytokines as well as phosphorylation levels of MAPK pathways. Mas receptor functions and underlying mechanisms were studied further in the human bronchial epithelial cell line (16HBE).. Mas receptor expression decreased in acute allergic airway inflammation. Multiplex immunofluorescence co-localized Mas receptor and EpCAM, indicated that Mas receptor may function in the bronchial epithelium. Activating Mas receptor through AVE0991 significantly alleviated macrophage infiltration in airway inflammation, accompanied with down-regulation of CCL2 and phosphorylation levels of MAPK pathways. Further studies in 16HBE showed that AVE0991 pre-treatment inhibited LPS-induced or anisomycin-induced CCL2 increase and THP-1 macrophages migration via JNK pathways.. Our findings suggested that Mas receptor activation significantly attenuated CCL2 dependent macrophage recruitments in acute allergic airway inflammation through JNK pathways, which indicated that Mas receptor, CCL2 and phospho-JNK could be potential targets against allergic airway inflammation.

Topics: Acute Disease; Angiotensin I; Animals; Asthma; Chemokine CCL2; Cytokines; Imidazoles; Inflammation; Macrophage Activation; Macrophages; Male; MAP Kinase Signaling System; Mice; Mice, Inbred BALB C; Ovalbumin; Peptide Fragments; Phosphorylation; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Respiratory System

We previously demonstrated that angiotensin-(1-7) (Ang-(1-7)), an essential endocrine factor, inhibits the NLRP3 inflammasome by regulating reactive oxygen species (ROS) in fibrotic livers. We also demonstrated that the NLRP3 inflammasome contributes to the liver damage induced by pyroptosis after heatstroke. However, the role of Ang-(1-7) in the hepatocytes under heat stress remains uncertain. We aimed to examine the change in angiotensin peptides in the livers affected by heatstroke and the effect on the ROS-NLRP3 inflammatory signalling pathway.

Topics: Angiotensin I; Angiotensin II; Animals; Biomarkers; Heat Stroke; Hepatocytes; Humans; Imidazoles; Inflammasomes; Inflammation; Interleukin-1beta; Liver; Liver Cirrhosis; Male; NLR Family, Pyrin Domain-Containing 3 Protein; Peptide Fragments; Prospective Studies; Pyroptosis; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Signal Transduction

During the aging process, chronic neuroinflammation induced by microglia is detrimental for the brain and contributes to the etiology of several aging-related neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. As a newly identified axis of renin-angiotensin system, ACE2/Ang-(1-7)/MAS1 axis plays a crucial role in modulating inflammatory responses under various pathological conditions. However, its relationship with aging-related neuroinflammation is less studied so far. In this study, by using SAMP8 mice, an animal model of accelerated aging, we revealed that the neuroinflammation in the aged brain might be attributed to a decreased level of Ang-(1-7). More importantly, we provided evidence that AVE0991, a nonpeptide analogue of Ang-(1-7), attenuated the aging-related neuroinflammation via suppression of microglial-mediated inflammatory response through a MAS1 receptor-dependent manner. Meanwhile, this protective effect might be ascribed to the M2 activation of microglia induced by AVE0991. Taken together, these findings reveal the association of Ang-(1-7) with the inflammatory response in the aged brain and uncover the potential of its nonpeptide analogue AVE0991 in attenuation of aging-related neuroinflammation.

Topics: Aging; Angiotensin I; Animals; Brain; Imidazoles; Inflammation; Mice; Microglia; Peptide Fragments; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled