title: Activation of the NLRP3 inflammasome by cellular labile iron.
abstract: Cellular labile iron, which contains chelatable redox-active Fe(2+), has been implicated in iron-mediated cellular toxicity leading to multiple organ dysfunction. Iron homeostasis is controlled by monocytes/macrophages through their iron recycling and storage capacities. Furthermore, iron sequestration by monocytes/macrophages is regulated by pro-inflammatory cytokines including interleukin-1, highlighting the importance of these cells in the crosstalk between inflammation and iron homeostasis. However, a role for cellular labile iron in monocyte/macrophage-mediated inflammatory responses has not been defined. Here we describe how cellular labile iron activates the NLRP3 inflammasome in human monocytes. Stimulation of lipopolysaccharide-primed peripheral blood mononuclear cells with ferric ammonium citrate increases the level of cellular Fe(2+) levels in monocytes and induces production of interleukin-1β in a dose-dependent manner. This ferric ammonium citrate-induced interleukin-1β production is dependent on caspase-1 and is significantly inhibited by an Fe(2+)-specific chelator. Ferric ammonium citrate consistently induced interleukin-1β secretion in THP1 cells, but not in NLRP3-deficient THP1 cells, indicating a requirement for the NLRP3 inflammasome. Additionally, activation of the inflammasome is mediated by potassium efflux, reactive oxygen species-mediated mitochondrial dysfunction, and lysosomal membrane permeabilization. Thus, these results suggest that monocytes/macrophages not only sequestrate iron during inflammation, but also mediate inflammation in response to cellular labile iron, which provides novel insights into the role of iron in chronic inflammation.
authors.affiliation: Department of Immunobiology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan; Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Kyohei
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Immunobiology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan; Department of Thoracic Surgery, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kawakami
authors.affiliation: Department of Immunobiology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Yamamoto
authors.affiliation: Department of Immunobiology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan.
authors.forename: Miyu
authors.initials: M
authors.lastname: Tomizawa
authors.affiliation: Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Tohru
authors.initials: T
authors.lastname: Fujiwara
authors.affiliation: Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Harigae
authors.affiliation: Department of Immunobiology, Institute of Development, Aging, and Cancer, Tohoku University, Sendai, Japan. Electronic address: ogasawara@idac.tohoku.ac.jp.
authors.forename: Kouetsu
authors.initials: K
authors.lastname: Ogasawara
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002460:Cell Line; D053583:Interleukin-1beta / Q000378:metabolism; D051379:Mice; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D017382:Reactive Oxygen Species
chemical_list: D002352:Carrier Proteins; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D017382:Reactive Oxygen Species