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

Autophagy. 2017 Oct 3;13(10):1664-1678. doi: 10.1080/15548627.2017.1345411. Epub 2017 Aug 18.

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.

Keywords: ALIS; CXCL10; DHA; IKBKB; IP10; IRF1; IRF3; KEAP1; LPS; MDM; NFE2L2; NFKB; OA; PUFA; SQSTM1; STAT1; TLR4; TNF; aggregates; omega-3; p62.

MeSH terms

  • Animals
  • Autophagy / drug effects
  • Autophagy / physiology
  • Cells, Cultured
  • Fatty Acids, Omega-3 / pharmacology*
  • Inclusion Bodies / drug effects*
  • Inclusion Bodies / genetics
  • Inclusion Bodies / metabolism
  • Inflammation / genetics
  • Inflammation / metabolism
  • Inflammation / prevention & control*
  • Inflammation Mediators / metabolism
  • Kelch-Like ECH-Associated Protein 1 / metabolism*
  • Macrophages / drug effects*
  • Macrophages / metabolism
  • Mice
  • Mice, Knockout
  • NF-E2-Related Factor 2 / metabolism*
  • Sequestosome-1 Protein / genetics
  • Sequestosome-1 Protein / metabolism*
  • Transcriptional Activation / drug effects

Substances

  • Fatty Acids, Omega-3
  • Inflammation Mediators
  • Keap1 protein, mouse
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Sequestosome-1 Protein
  • Sqstm1 protein, mouse