Abstract
Microglia, a type of immune cell in the central nervous system, are involved in inflammation leading to neurodegenerative diseases. We previously identified oleamide from fermented dairy products as a neuroprotective compound suppressing microglial inflammation. Oleamide is an endocannabinoid and displays anti-inflammatory activity via the cannabinoid-2 (CB2) receptor; however, the mechanism underlying this anti-inflammatory activity has not been fully elucidated. Here, we found that the suppressive effect of oleamide on microglial tumor necrosis factor-α (TNF-α) production was canceled by inhibitors of G-protein-coupled receptor (GPCR) downstream signaling but not by a CB2 antagonist, suggesting that GPCRs other than CB2 are involved in the anti-inflammatory effects of oleamide. An extensive screen for GPCRs using a transforming growth factor-α shedding assay system identified P2Y1, P2Y4, P2Y6, P2Y10, and P2Y11 as candidates for the oleamide target. P2Y1 and P2Y10 agonists suppressed microglial TNF-α production, while a pan P2 receptor antagonist canceled the suppressive effect. Furthermore, we observed a relationship between the P2Y1 agonistic activities and the suppressive activities of oleamide and its analogs. Taken together, our results suggest that, in addition to CB2, P2Y type receptors are the potential targets of oleamide, and P2Y1 plays a role in the suppression of microglial inflammatory responses by oleamide. (200/200 words)
Highlights
In neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, and depression, chronic inflammation featuring excessive activation of microglia is closely involved in the pathogenesis[1,2,3]
Less suppression of microglial tumor necrosis factor-α (TNF-α) production by OAD was observed for cells treated with JTE907 (Fig. 1A), showing that CB2 is involved in the suppression of TNF-α by OAD; the difference between cells with and without JTE907 did not reach significance; in other words, treatment with JTE907 did not completely attenuate the effect of OAD on microglia
To elucidate the anti-inflammatory activity of OAD in human monocytes including dendritic cells (DCs) and microglia, human DCs differentiated from peripheral blood mononuclear cells (PBMCs) were treated with OAD followed by LPS
Summary
In neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, and depression, chronic inflammation featuring excessive activation of microglia is closely involved in the pathogenesis[1,2,3]. An accumulation of amyloid-β and chronic psychological stress result in overactivation of microglia, which release an excess of inflammatory cytokines including TNF-α and reactive oxygen species (ROS), leading to neuronal cell death and neurodegenerative disease. OAD, which is synthesized from oleic acid by Penicillium candidum during fermentation, suppresses microglial production of TNF-α in response to lipopolysaccharide (LPS) stimulation, as well as the expression of inflammatory cell markers, in vitro and in vivo. Treatment with cannabinoids suppresses microglial TNF-α production in response to LPS stimulation[10], and some of the anti-inflammatory effects of OAD are dependent on CB2 activation[11]. The anti-inflammatory activity of OAD, and OAD displays a synergistic effect with other CB2 agonists[11] These reports have encouraged us to explore potential receptors for OAD other than CB2. A series of GPCR screens were conducted by using a transforming growth factor-α (TGF-α) shedding assay[12], and the identified GPCRs were evaluated for their involvement in the anti-inflammatory effects of OAD in primary murine microglia and human dendritic cells (DCs)
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