A novel fatty acid analogue triggers CD36-GPR120 interaction and exerts anti-inflammatory action in endotoxemia.
Pierre-Marie BoutanquoiAmira Sayed KhanLidia CabezaLucas JantzenThomas GautierSemen YesylevskyyChristophe RamseyerDavid MassonVincent Van WaesAziz HichamiNaim Akhtar KhanPublished in: Cellular and molecular life sciences : CMLS (2024)
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.
Keyphrases
- lps induced
- inflammatory response
- fatty acid
- anti inflammatory
- nitric oxide
- rheumatoid arthritis
- lipopolysaccharide induced
- induced apoptosis
- oxidative stress
- protein protein
- septic shock
- type diabetes
- toll like receptor
- cardiovascular disease
- risk factors
- cell death
- high throughput
- endoplasmic reticulum stress
- coronary artery disease
- poor prognosis
- cardiovascular events
- metabolic syndrome
- molecular dynamics simulations
- traumatic brain injury
- wild type
- subarachnoid hemorrhage
- smoking cessation
- nitric oxide synthase