N-3 PUFAs induce inflammatory tolerance by formation of KEAP1-containing SQSTM1/p62-bodies and activation of NFE2L2

Abstract

Inflammation is crucial in the defense against infections but must be tightly controlled to limit detrimental hyperactivation. Our diet influences inflammatory processes and omega-3 polyunsaturated fatty acids (n-3 PUFAs) have known anti-inflammatory effects. The balance of pro- and anti-inflammatory processes is coordinated by macrophages and macroautophagy/autophagy has recently emerged as a cellular process that dampens inflammation. Here we report that the n-3 PUFA docosahexaenoic acid (DHA) transiently induces cytosolic speckles of the autophagic receptor SQSTM1/p62 (sequestosome 1) (described as SQSTM1/p62-bodies) in macrophages. We suggest that the formation of SQSTM1/p62-bodies represents a fast mechanism of NFE2L2/Nrf2 (nuclear factor, erythroid 2 like 2) activation by recruitment of KEAP1 (kelch like ECH associated protein 1). Further, the autophagy receptor TAX1BP1 (Tax1 binding protein 1) and ubiquitin-editing enzyme TNFAIP3/A20 (TNF α induced protein 3) could be identified in DHA-induced SQSTM1/p62-bodies. Simultaneously, DHA strongly dampened the induction of pro-inflammatory genes including CXCL10 (C-X-C motif chemokine ligand 10) and we suggest that formation of SQSTM1/p62-bodies and activation of NFE2L2 leads to tolerance towards selective inflammatory stimuli. Finally, reduced CXCL10 levels were related to the improved clinical outcome in n-3 PUFA-supplemented heart-transplant patients and we propose CXCL10 as a robust marker for the clinical benefits mobilized by n-3 PUFA supplementation.

Organic extracts from Cleome droserifolia exhibit effective caspase-dependent anticancer activity

“…Autophagy has been shown to cause cell death along with apoptosis or ensure cell survival by inhibiting apoptosis [68]. Interestingly, it may even be a requirement for activating apoptosis in cells which are faced with stresses that can activate autophagy itself, such as oxidative stress or nutrient depravation [69,70]. Thus, although we observed activation of autophagy in the case of CDD as well as other plant organic fractions [52,53], it is not clear whether it was a requirement or a consequence of apoptotic cell death, manifesting as a cell survival response.…”

“…Thus, although we observed activation of autophagy in the case of CDD as well as other plant organic fractions [52,53], it is not clear whether it was a requirement or a consequence of apoptotic cell death, manifesting as a cell survival response. For example, it has been shown that oligomerization of SQATM1/p62 by oxidative stress is suggestive of induction of autophagy as a pro-survival mechanism rather than a cell death process [69,70]. Alternatively, it could also be an independent response to compounds in CDD or the other plant extracts.…”

A Higher Proportion of Eicosapentaenoic Acid (EPA) When Combined with Docosahexaenoic Acid (DHA) in Omega-3 Dietary Supplements Provides Higher Antioxidant Effects in Human Retinal Cells

“…Recent research has demonstrated that the long chain n-3 PUFA, has antiangiogenic, anti-vasoproliferative, and neuroprotective actions on factors and processes implicated in the pathogenesis of degenerative/vascular retinal diseases of greatest public significance, including DR [ 18 ]. It has been demonstrated that diets with high levels of n-3 PUFA, have known anti-inflammatory properties [ 36 ] due to their ability to promote the gene expression of various inflammatory mediators via different intracellular signaling pathways [ 37 ] leading to the inhibition of the expressions of pro-inflammatory cytokines, leukocyte chemotaxis, and adhesion molecules. It is also known that they regulate the production of eicosanoids such as prostaglandins and leukotrienes and increase the synthesis of anti-inflammatory mediators such as resolvins, protectins, and maresins [ 38 ].…”

Analysis of Genetically Determined Gene Expression Suggests Role of Inflammatory Processes in Etiology of Exfoliation Syndrome

“…[60][61][62] Omega fatty acid has been suggested as an IOP reducing supplements [63][64][65] because of its anti-inflammatory effects. 66 Association of steroid derivative, estrogen with glaucoma has been previously explored with higher levels of estrogen in reduction in IOP and conferring a possible reduced risk of glaucoma. 67 The synthetic form of estrogen, estradiol, has been shown in a rat glaucoma model to inhibit optic nerve axonal degeneration by inducing a protein that is crucial in protecting RGC from oxidative damage.…”