Follistatin-like protein 1 enhances NLRP3 inflammasome-mediated IL-1β secretion from monocytes and macrophages.
Follistatin-like protein 1 (FSTL-1) is overexpressed in a number of inflammatory conditions characterized by elevated IL-1β. Here, we found that FSTL-1 serum concentration was increased threefold in patients with bacterial sepsis and fourfold following administration of LPS to mice. To test the contribution of FSTL-1 to IL-1β secretion, WT and FSTL-1-deficient mice were injected with LPS. While LPS induced IL-1β in the sera of WT mice, it was low or undetectable in FSTL-1-deficient mice. Monocytes/macrophages, a key source of IL-1β, do not normally express FSTL-1. However, FSTL-1 was found in tissue macrophages after injection of LPS into mouse footpads, demonstrating that macrophages are capable of taking up FSTL-1 at sites of inflammation. In vitro, intracellular FSTL-1 localized to the mitochondria. FSTL-1 activated the mitochondrial electron transport chain, increased the production of ATP (a key activator of the nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome) and IL-1β secretion. FSTL-1 also enhanced transcription of the NLRP3 and procaspase 1 genes, two components of the NLRP3 inflammasome. Adenovirus-mediated overexpression of FSTL-1 in mouse paws led to activation of the inflammasome complex and local secretion of IL-1β and IL-1β-related proinflammatory cytokines. These results suggest that FSTL-1 may act on the NLRP3 inflammasome to promote IL-1β secretion from monocytes/macrophages.
Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
Yury
Y
Chaly
Yu
Y
Fu
Anthony
A
Marinov
Bruce
B
Hostager
Wei
W
Yan
Brian
B
Campfield
John A
JA
Kellum
Daniel
D
Bushnell
Yudong
Y
Wang
Jerry
J
Vockley
Raphael
R
Hirsch
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020170:Caspase 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D038702:Follistatin-Related Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D058847:Inflammasomes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D009000:Monocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020298:U937 Cells
D002352:Carrier Proteins; D038702:Follistatin-Related Proteins; C448720:Fstl1 protein, mouse; C508585:IL1B protein, human; D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; C492716:Nlrp3 protein, mouse; C448799:FSTL1 protein, human; D020170:Caspase 1
Cytokines; Follistatin-like protein 1; Inflammasome; Macrophages; Monocytes