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N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation via Nonhematopoietic TRPV1.

ABSTRACT: N-Arachidonoyl dopamine (NADA) is an endogenous lipid that potently activates the transient receptor potential vanilloid 1 (TRPV1), which mediates pain and thermosensation. NADA is also an agonist of cannabinoid receptors 1 and 2. We have reported that NADA reduces the activation of cultured human endothelial cells by LPS and TNF-α. Thus far, in vivo studies using NADA have focused on its neurologic and behavioral roles. In this article, we show that NADA potently decreases in vivo systemic inflammatory responses and levels of the coagulation intermediary plasminogen activator inhibitor 1 in three mouse models of inflammation: LPS, bacterial lipopeptide, and polymicrobial intra-abdominal sepsis. We also found that the administration of NADA increases survival in endotoxemic mice. Additionally, NADA reduces blood levels of the neuropeptide calcitonin gene-related peptide but increases the neuropeptide substance P in LPS-treated mice. We demonstrate that the anti-inflammatory effects of NADA are mediated by TRPV1 expressed by nonhematopoietic cells and provide data suggesting that neuronal TRPV1 may mediate NADA's anti-inflammatory effects. These results indicate that NADA has novel TRPV1-dependent anti-inflammatory properties and suggest that the endovanilloid system might be targeted therapeutically in acute inflammation.

SUBMITTER: Lawton SK

PROVIDER: S-EPMC5544930 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Acute inflammation (INF) and apoptosis are induced in monocytes by the generation of several factors, including the products of cytosolic oxygen free radicals (cROS) and the excessive influx of Ca2+ via the stimulation of TRPV1. These are main factors in the etiology of monocyte activation-induced inflammatory and neurodegenerative diseases. Importantly, the protective action of hydroxychloroquine (HCQ) treatment via the inhibition of TRPV1 on the levels of inflammatory factors, cROS, and apoptosis in acute INF (lipopolysaccharide, LPS)-exposed neuronal cells was recently reported. However, the relationships between acute INF via TRPV1 activation and HCQ in monocytes have not been fully clarified yet. The cell membrane of U937 human monocytes contains natural TRPV1. In the study plan, we used U937 cells in four main groups, namely control, HCQ (60 μM for 48 h), INF (1 μg/mL LPS for 16 h), and HCQ + INF. The current data indicate that LPS-induced acute INF caused the upregulation of excessive cytosolic Ca2+ accumulation via the stimulation of TRPV1 in the cells. The treatment of INF additionally upregulated the levels of apoptosis and cytokines (IL6, IL1β, and TNFα), due to upregulated cROS and lipid peroxidation levels as well as upregulated generation of caspase -3 (CAS3) and -9 (CAS9) but a decrease in glutathione and glutathione peroxidase. The expression levels of TRPV1, Bax, CAS3, and CAS9 were also upregulated by the treatment of LPS. However, treatment with HCQ and TRPV1 blocker (capsazepine) modulated the levels of cytokines, caspases, cROS, Ca2+ influx, and apoptosis through the modulation of TRPV1 in the U937 that were stimulated with LPS. In summary, the present data suggest TRPV1 activation through the acute INF (LPS)-induced inflammatory, oxidant, and apoptotic adverse actions in monocyte cells, whereas HCQ prevented adverse actions via the modulation of TRPV1. The results may be significant in the modulation of monocyte activation-caused inflammatory and neurodegenerative diseases.

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N-Arachidonoyl Dopamine Modulates Acute Systemic Inflammation via Nonhematopoietic TRPV1.

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