Soluble epoxide hydrolase inhibition enhances production of specialized pro‐resolving lipid mediator and promotes macrophage plasticity

Abstract

Background and Purpose: Epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids (EpFA) are lipid mediators that are rapidly inactivated by soluble epoxide hydrolase (sEH). Uncontrolled and chronic inflammatory disorders fail to sufficiently activate endogenous regulatory pathways, including the production of specialized proresolving mediators (SPMs). Here, we addressed the relationship between SPMs and the EET/sEH axis and explored the effects of sEH inhibition on resolving macrophage phenotype.Experimental Approach: Mice were treated with a sEH inhibitor, EETs, or sEH inhibitor + EETs (combination) before ligature placement to induce experimental periodontitis. Using RT-qPCR, gingival samples were used to examine SPM receptors and osteolytic and inflammatory biomarkers. Maxillary alveolar bone loss was quantified by micro-CT and methylene blue staining. SPM levels were analysed by salivary metabolo-lipidomics. Gingival macrophage phenotype plasticity was determined by RT-qPCR and flow cytometry. Effects of sEH inhibition on macrophage polarization and SPM production were assessed with bone marrow-derived macrophages (BMDMs).

Small Molecule Activation of NAPE-PLD Enhances Efferocytosis by Macrophages

“…Three of the 399 identified activators (Table 1, entries 1-3) shared a common benzothiazole phenylsulfonyl-piperidine carboxamide (BT-PSP) core structure. To determine if this series of benzothiazoles might serve as a tractable lead for the development of activators as chemical probes, we obtained additional structurally similar compounds using a combination of targeted purchasing of commercial molecules (Table 1, entries 4-13) and discrete chemical synthesis (Table 1, entries [14][15][16][17][18][19][20][21][22]. The activity of this series of 22 benzothiazole phenylsulfonyl-piperidine carboxamides thus obtained was assessed for enzyme activation using recombinant mouse Nape-pld (Supplemental Figure 1 and Table 1).…”

The impact of the soluble epoxide hydrolase cascade on periodontal tissues

“…In macrophages, the pharmacological inhibition of soluble epoxide hydrolase stimulated a dynamic transcriptional reprogramming of inflammatory macrophages toward resolving macrophages (characterized by CD11c + /CD206 + double-positive cells in the CD45 + /CD11b + /CD64 + macrophage population), associated with reduced expression of Il1β, TNFα, Il12, and Nos2. Finally, in vitro assay revealed that sEH inhibition and EET treatment triggered SPM release in bone marrow derived macrophages (BMDMs) in both inflammatory and resolvents macrophages (23). These findings are summarized in Figure 2.…”

“…The pharmacological inhibition of soluble epoxide hydrolase and its impact on inflammatory, autoimmune, and pain disorders has been widely explored (63)(64)(65)(66). Nevertheless, its application in periodontitis or other orofacial conditions is new (18,(21)(22)(23)67). There are only a few studies involving the inhibition of the soluble epoxide hydrolase enzyme in periodontal disease (21-23); therefore, we will address them in detail.…”

“…Recently, Abdalla and coworkers thoroughly characterized the impact of the sEH/EET axis on gingival macrophage plasticity in experimental periodontitis in mice. The work revealed for the first time that pharmacological inhibition of sEH fosters communication between epoxy fatty acid metabolites, increasing the levels of Specialized Pro-Resolving Mediators [e.g., resolvin (Rv) E-series and lipoxins] in saliva, as well as their respective receptors in the gingival tissues (23).…”

“…Worst, some of their diols contribute to inflammatory cytokine storm and block the initiation of the resolution phase (17). The sEH enzymes are largely found in liver, brain, spleen, kidney, intestine, and joints (18)(19)(20), and high sEH expression was detected in chronic osteolytic inflammatory disorders, such as periodontitis and arthritis (19,(21)(22)(23).…”