Saturated fatty acids activate caspase-4/5 in human monocytes, triggering IL-1β and IL-18 release

Nicolas J. Pillon, Kenny L. Chan, Shitian Zhang, Marios Mejdani, Maya R. Jacobson, Alexandre Ducos, Philip J. Bilan, Wenyan Niu, Amira Klip

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

Abstract

Obesity is associated with metabolic tissue infiltration by monocytederived macrophages. Saturated fatty acids contribute to proinflammatory gene induction in tissue-embedded immune cells. However, it is unknown how circulating monocytes, the macrophage precursors, react to high-fat environments. In macrophages, saturated fatty acids activate inflammatory pathways and, notably, prime caspase-associated inflammasomes. Inflammasome-activated IL-1β contributes to type 2 diabetes. We hypothesized that 1) human monocytes from obese patients show caspase activation, and 2) fatty acids trigger this response and consequent release of IL-1β/IL-18. Human peripheral blood monocytes were sorted by flow cytometry, and caspase activity was measured with a FLICA dye-based assay. Blood monocytes from obese individuals exhibited elevated caspase activity. To explore the nature and consequence of this activity, human THP1 monocytes were exposed to saturated or unsaturated fatty acids. Caspase activity was revealed by isoform-specific cleavage and enzymatic activity; cytokine expression/release was measured by qPCR and ELISA. Palmitate, but not palmitoleate, increased caspase activity in parallel to the release of IL-1β and IL-18. Palmitate induced eventual monocyte cell death with features of pyroptosis (an inflammation-linked cell death program involving caspase-4/5), scored through LDH release, vital dye influx, cell volume changes, and nuclear morphology. Notably, selective gene silencing or inhibition of caspase-4/5 reduced palmitate-induced release of IL-1β and IL-18. In summary, monocytes from obese individuals present elevated caspase activity. Mechanistically, palmitate activates a pyroptotic program in monocytes through caspase-4/5, causing inflammatory cytokine release, additional to inflammasomes. These caspases represent potential, novel, therapeutic targets to taper obesity-associated inflammation.

Original languageEnglish
Pages (from-to)E825-E835
JournalAmerican Journal of Physiology - Endocrinology and Metabolism
Volume311
Issue number5
DOIs
StatePublished - 2016
Externally publishedYes

Keywords

  • Caspase
  • Fatty acids
  • Inflammation
  • Interleukin-1β
  • Monocytes
  • Palmitate
  • Pyroptosis
  • THP-1

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