Fenretinide Corrects the Imbalance between Omega-6 to Omega-3 Polyunsaturated Fatty Acids and Inhibits Macrophage Inflammatory Mediators via the ERK Pathway

Abstract

We previously identified Fragile X-related protein 1 (FXR1) as an RNA-binding protein involved in the post-transcriptional control of TNF and other cytokines in macrophages. Macrophages derived from FXR1-KO mice overexpress several inflammatory cytokines including TNF. Recently, we showed that fenretinide (4HPR) is able to inhibit several inflammatory cytokines in the lungs of cystic fibrosis mice, which also have abnormal immune responses. Therefore, we hypothesized that 4HPR might also be able to downregulate excessive inflammation even in macrophages with ablated FXR1. Indeed, our results demonstrate that 4HPR inhibited the excessive production of inflammatory mediators, including TNF, IL-6, CCL2 and CCL-5 in LPS-stimulated FXR1-KO macrophages, by selectively inhibiting phosphorylation of ERK1/2, which is naturally more phosphorylated in FXR1-KO cells. We also found that LPS stimulation of FXR1-KO macrophages led to significantly higher ratio of arachidonic acid/docosahexaenoic acid than observed in FXR1-WT macrophages. Interestingly, treatment with 4HPR was associated with the normalization of arachidonic acid/docosahexaenoic acid ratio in macrophages, which we found to impact phosphorylation of ERK1/2. Overall, this study shows for the first time that 4HPR modulates inflammatory cytokine expression in macrophages by correcting a phospholipid-bound fatty acid imbalance that impacts the phosphorylation of ERK1/2.

Deregulated Balance of Omega-6 and Omega-3 Polyunsaturated Fatty Acids following Infection by the Zoonotic Pathogen Streptococcus suis

“…We and others previously showed that ERK1/2 MAPK is activated following infection by S. suis (27,31). We have also previously demonstrated that fenretinide is able to downregulate ERK1/2 phosphorylation in LPS-treated macrophages (32). In the present study, macrophages pretreated with fenretinide prior to S. suis infection showed a significant reduction in ERK1/2 activation compared to nontreated S. suis-infected macrophages (Fig.…”

Treatment of Allergic Asthma with Fenretinide Formulation (LAU-7b) Downregulates ORMDL Sphingolipid Biosynthesis Regulator 3 (Ormdl3) Expression and Normalizes Ceramide Imbalance

“…Our studies clearly demonstrate that treatment of allergen-sensitized and allergenchallenged mice with LAU-7b had lower expression of Il-4 (WT mice), Il-5 and Eotaxin-1 (WT and KO mice) compared to PBS-treated mice which is consistent with the previously reported effect on ERK1/2 phosphorylation (Lachance et al 2013). IL-13 is a key regulatory cytokine in the production of IgE (Rael et al 2011).…”

Fenretinide treatment accelerates atherosclerosis development in apoE‐deficient mice in spite of beneficial metabolic effects

“…For the glucose tolerance test, after 10 weeks of treatment, mice were fasted for 5 hr and then injected with 2 g·kg −1 glucose via intraperitoneal injection of 20% w/v sterile glucose solution in PBS. Glucose levels were determined as described previously (Lachance et al, ).…”