title: Hemin and Cobalt Protoporphyrin Inhibit NLRP3 Inflammasome Activation by Enhancing Autophagy: A Novel Mechanism of Inflammasome Regulation.
abstract: Inflammasomes are intracellular protein platforms, which, upon activation, produce the highly proinflammatory cytokines interleukin (IL)-1β and IL-18. Heme, hemin and their degradation products possess significant immunomodulatory functions. Here, we studied whether hemin regulates inflammasome function in macrophages. Both hemin and its derivative, cobalt protoporphyrin (CoPP), significantly reduced IL-1β secretion by cultured human primary macrophages, the human monocytic leukemia cell line and also mouse bone marrow-derived and peritoneal macrophages. Intraperitoneal administration of CoPP to mice prior to urate crystal-induced peritonitis alleviated IL-1β secretion to the peritoneal cavity. In cultured macrophages, hemin and CoPP inhibited NLRP3 inflammasome assembly by reducing the amount of intracellular apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC). The reduction of ASC was associated with enhanced autophagosome formation and autophagic flux. Inhibition of autophagy prevented the CoPP-induced depletion of ASC, implying that the depletion was caused by increased autophagy. Our data indicate that hemin functions as an endogenous negative regulator of the NLRP3 inflammasome. The inhibition is mediated via enhanced autophagy that results in increased degradation of ASC. This regulatory mechanism may provide a novel approach for the treatment of inflammasome-related diseases.
authors.affiliation: Wihuri Research Institute, Helsinki, Finland.
authors.forename: Katariina
authors.initials: K
authors.lastname: Nurmi
authors.forename: Ilona
authors.initials: I
authors.lastname: Kareinen
authors.forename: Juhani
authors.initials: J
authors.lastname: Virkanen
authors.forename: Kristiina
authors.initials: K
authors.lastname: Rajamäki
authors.forename: Vesa-Petteri
authors.initials: VP
authors.lastname: Kouri
authors.forename: Kirsi
authors.initials: K
authors.lastname: Vaali
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Levonen
authors.forename: Nanna
authors.initials: N
authors.lastname: Fyhrquist
authors.forename: Sampsa
authors.initials: S
authors.lastname: Matikainen
authors.forename: Petri T
authors.initials: PT
authors.lastname: Kovanen
authors.forename: Kari K
authors.initials: KK
authors.lastname: Eklund
mesh_terms: D000818:Animals; D002460:Cell Line; D006427:Hemin / Q000008:administration & dosage / Q000378:metabolism*; D006801:Humans; D056747:Immunomodulation; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism; D010538:Peritonitis / Q000139:chemically induced / Q000276:immunology*; D011524:Protoporphyrins / Q000008:administration & dosage / Q000378:metabolism*; D014527:Uric Acid
chemical_list: D058847:Inflammasomes; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D011524:Protoporphyrins; D014527:Uric Acid; C007095:cobaltiprotoporphyrin; D006427:Hemin