Fig. 6

Endogenous neurolipid modulation during acute inflammation and the effects of exogenous OLDA on neuroinflammatory mediators. A Regulation of endogenous neurolipids, including arachidonic acid and its metabolites (prostaglandin, leukotriene B4, eicosapentaenoic acid, hydroxyeicosatetraenoic acid and octadecadienoic acid) and conjugation products (N-acyl dopamines, acyl-glycerol and N-acylethanolamines) following LPS ± exogenous vanilloid (OLDA) injection. LPS injection provoked acute changes in N-acyl-dopamines and acyl-ethanolamines in brain and plasma: Wild-type mice were challenged with LPS (3 mg/kg, i.v.) ± OLDA (10 mg/kg, i.v.). Brain and plasma were harvested at 10, 30 and 120 min (12-week male, n = 4–8 mice per time point, respectively, at 0, 10, 30 and 120 min after LPS injection). A1 In the brain, arachidonic acid and its hydroxyeicosatetraenoic acid (HETE) metabolites were significantly downregulated during acute inflammation. A2, B Conversely, arachidonic acid metabolites from the prostaglandin (PD2, PE2 and D12PJ2) leukotriene B4, eicosapentaenoic and octadecadienoic acid families were upregulated. OLDA was barely detectable at baseline, in brain and plasma and trended towards increased in blood and plasma during the first 120 min following LPS injection, as did acyl-glycerol (1-AG, 2-AGE) and N-acylethanolamines in the plasma. Results are shown as a heat map, baseline levels being considered as reference (100%) for each metabolite (12-week male, n = 4–8 mice per time point, respectively, at 0, 10, 30 and 120 min after LPS injection). C Changes in levels of hormones or peptide neuromodulators in C1 total brain extracts and C2 plasmas from wild-type mice, at baseline and 2 h after i.v. challenge with LPS (1 mg/kg) followed by either OLDA (10 mg/kg) or carrier (9-week male, n = 4/group for cortisol, dopamine, substance P and neurotensin; 10-week-old male, 13-week female, n = 7–10/group for GABA; 8- to 9-week female, n = 6–9/group for glutamate). D The vanilloid neuro-immune anti-inflammatory reflex does not require the spleen: Splenectomy performed 3 weeks prior to induction of endotoxemia and treatment with OLDA did not abrogate the anti-inflammatory effects of OLDA. These results suggest that the neuro-immune action of OLDA is independent of the vagal–splenic anti-inflammatory pathway, and that bone marrow rather than spleen Mo-MDSCs produce IL-10 in response to co-treatment with LPS + OLDA. Plasma cytokines were quantified in plasma at T = 2 h after LPS challenge (1 mg/kg i.v.) and OLDA (10 mg/kg i.v.) or carrier (i.v.) (12- to 13-week male, n = 5–8/group). **P < 0.01, ***P < 0.001, LPS-treated mice vehicle vs. OLDA, two-tailed Mann–Whitney U test