N-acylethanolamine regulation of TLR3-induced hyperthermia and neuroinflammatory gene expression: A role for PPARα

Abstract

Increasing evidence suggests that SARS-CoV-2, the virus responsible for the COVID-19 pandemic, is associated with increased risk of developing neurological or psychiatric conditions such as depression, anxiety or dementia. While the precise mechanism underlying this association is unknown, aberrant activation of toll-like receptor (TLR)3, a viral recognizing pattern recognition receptor, may play a key role. Synthetic cannabinoids and enhancing cannabinoid tone via inhibition of fatty acid amide hydrolase (FAAH) has been demonstrated to modulate TLR3-induced neuroimmune responses and associated sickness behaviour. However, the role of individual FAAH substrates, and the receptor mechanisms mediating these effects, are unknown. The present study examined the effects of intracerebral or systemic administration of the FAAH substrates N -oleoylethanolamide (OEA), N -palmitoylethanolamide (PEA) or the anandamide (AEA) analogue meth-AEA on hyperthermia and hypothalamic inflammatory gene expression following administration of the TLR3 agonist, and viral mimetic, poly I:C. The data demonstrate that meth-AEA does not alter TLR3-induced hyperthermia or hypothalamic inflammatory gene expression. In comparison, OEA and PEA attenuated the TLR3-induced hyperthermia, although only OEA attenuated the expression of hyperthermia-related genes ( IL-1β, iNOS, COX2 and m-PGES ) in the hypothalamus. OEA, but not PEA, attenuated TLR3-induced increases in the expression of all IRF- and NFκB-related genes examined in the hypothalamus, but not in the spleen. Antagonism of PPARα prevented the OEA-induced attenuation of IRF- and NFκB-related genes in the hypothalamus following TLR3 activation but did not significantly alter temperature. PPARα agonism did not alter TLR3-induced hyperthermia or hypothalamic inflammatory gene expression. These data indicate that OEA may be the primary FAAH substrate that modulates TLR3-induced neuroinflammation and hyperthermia, effects partially mediated by PPARα.

Tick-borne encephalitis virus transmitted singly and in duo with Borrelia burgdorferi sensu lato and Anaplasma phagocytophilum bacteria by ticks as pathogens modifying lipid metabolism in human blood

“…This seems to be confirmed by the results of the present study, which indicate significantly less activation of PPARγ in the case of co-infection than in the case of TBEV infection alone. In contrast to other viral diseases such as COVID-19, it has been suggested that OEA, which is also upregulated only in TBE patients, is responsible for the downregulation of NFκB-related gene expression [ 52 ] and also modulates the effects partially mediated by PPARα [ 53 ]. In addition, in patients with COVID-19, it was found that activation of the endocannabinoid system reduces viral replication and the level of pro-inflammatory cytokines [ 54 ], hence a similar response of the endocannabinoid system, especially in the case of TBE, but also partially in co-infections, can be considered beneficial and even pro- survival effect on the infected organism.…”

Blood gene expression predicts intensive care unit admission in hospitalised patients with COVID-19

“…Where PEA is also able to inhibit SARS-CoV-2 entry and replication ( 50 ). Interestingly, others have identified PPAR-α as a potential mediator neuroinflammation in COVID-19 ( 51 ). The third Top pathway had peak gene FAM89B, representing TGFβ signalling pathway, which is also associated with pulmonary fibrosis ( 52 ).…”

Toll-Like Receptor Signaling in Severe Acute Respiratory Syndrome Coronavirus 2-Induced Innate Immune Responses and the Potential Application Value of Toll-Like Receptor Immunomodulators in Patients With Coronavirus Disease 2019

“…Similarly, famotidine, a specific histamine H2 receptor antagonist, can inhibit TLR3 expression in SARS-CoV-2 infected cells and reduce TLR3-dependent NF-κB and IRF3 signaling, subsequently controlling antiviral and inflammatory responses ( Mukherjee et al, 2021 ) and reducing the risk of intubation and death in hospitalized patients with COVID-19 ( Freedberg et al, 2020 ). Another TLR signaling inhibitor, the PPARα agonist oleoylethanolamide (OEA), was reported to attenuate TLR3-induced hyperthermia and reduce the expression of hyperthermia-related genes including IL-1β, iNOS, COX2, and m-PGES in the hypothalamus ( Flannery et al, 2021 ).…”