Inflammation is a mediator of a number of chronic pathologies. We synthesized the diethyl (9Z,12Z)-octadeca-9,12-dien-1-ylphosphonate, called NKS3, which decreased lipopolysaccharide (LPS)-induced mRNA upregulation of proinflammatory cytokines (IL-1β, IL-6 and TNF-α) not only in primary intraperitoneal and lung alveolar macrophages, but also in freshly isolated mice lung slices. The in-silico studies suggested that NKS3, being CD36 agonist, will bind to GPR120. Co-immunoprecipitation and proximity ligation assays demonstrated that NKS3 induced protein-protein interaction of CD36 with GPR120in RAW 264.7 macrophage cell line. Furthermore, NKS3, via GPR120, decreased LPS-induced activation of TAB1/TAK1/JNK pathway and the LPS-induced mRNA expression of inflammatory markers in RAW 264.7 cells. In the acute lung injury model, NKS3 decreased lung fibrosis and inflammatory cytokines (IL-1β, IL-6 and TNF-α) and nitric oxide (NO) production in broncho-alveolar lavage fluid. NKS3 exerted a protective effect on LPS-induced remodeling of kidney and liver, and reduced circulating IL-1β, IL-6 and TNF-α concentrations. In a septic shock model, NKS3 gavage decreased significantly the LPS-induced mortality in mice. In the last, NKS3 decreased neuroinflammation in diet-induced obese mice. Altogether, these results suggest that NKS3 is a novel anti-inflammatory agent that could be used, in the future, for the treatment of inflammation-associated pathologies.

Department of Physical Chemistry Faculty of Science Palacký University Olomouc 17 listopadu 12 771 46 Olomouc Czech Republic

Department of Physics of Biological Systems Institute of Physics of the National Academy of Sciences of Ukraine Prospect Nauky 46 Kiev 03028 Ukraine

FCS Bourgogne Franche Comté LipSTIC LabEx Dijon France

Institute of Organic Chemistry and Biochemistry Czech Academy of Sciences 166 10 Prague 6 Czech Republic

Laboratoire Chrono Environnement UMR CNRS6249 Université de Bourgogne Franche Comté 16 route de Gray 25030 Besançon Cedex France

Laboratoire de Recherches Intégratives en Neurosciences et Psychologie Cognitive UR LINC UFC Besançon France

LIPNESS UMR U1231 INSERM UB Agro Sup Université Bourgogne Franche Comté 21000 Dijon France

Physiologie de la Nutrition and Toxicologie UMR U1231 INSERM Université de Bourgogne Agro Sup Université Bourgogne Franche Comté 6 Boulevard Gabriel 21000 Dijon France

Receptor AI Inc 20 22 Wenlock Road London N1 7GU UK

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