title: The Nlrp3 inflammasome, IL-1β, and neutrophil recruitment are required for susceptibility to a nonhealing strain of Leishmania major in C57BL/6 mice.
abstract: Infection of C57BL/6 mice with most Leishmania major strains results in a healing lesion and clearance of parasites from the skin. Infection of C57BL/6 mice with the L. major Seidman strain (LmSd), isolated from a patient with chronic lesions, despite eliciting a strong Th1 response, results in a nonhealing lesion, poor parasite clearance, and complete destruction of the ear dermis. We show here that in comparison to a healing strain, LmSd elicited early upregulation of IL-1β mRNA and IL-1β-producing dermal cells and prominent neutrophil recruitment to the infected skin. Mice deficient in Nlrp3, apoptosis-associated speck-like protein containing a caspase recruitment domain, or caspase-1/11, or lacking IL-1β or IL-1 receptor signaling, developed healing lesions and cleared LmSd from the infection site. Mice resistant to LmSd had a stronger antigen-specific Th1 response. The possibility that IL-1β might act through neutrophil recruitment to locally suppress immunity was supported by the healing observed in neutropenic Genista mice. Secretion of mature IL-1β by LmSd-infected macrophages in vitro was dependent on activation of the Nlrp3 inflammasome and caspase-1. These data reveal that Nlrp3 inflammasome-dependent IL-1β, associated with localized neutrophil recruitment, plays a crucial role in the development of a nonhealing form of cutaneous leishmaniasis in conventionally resistant mice.
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Melanie
authors.initials: M
authors.lastname: Charmoy
authors.affiliation: Department of Biochemistry, WHO-Immunology Research and Training Center, University of Lausanne, Lausanne, Switzerland.
authors.forename: Benjamin P
authors.initials: BP
authors.lastname: Hurrell
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Audrey
authors.initials: A
authors.lastname: Romano
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Sang Hun
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Flavia
authors.initials: F
authors.lastname: Ribeiro-Gomes
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Riteau
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Katrin
authors.initials: K
authors.lastname: Mayer-Barber
authors.affiliation: Department of Biochemistry, WHO-Immunology Research and Training Center, University of Lausanne, Lausanne, Switzerland.
authors.forename: Fabienne
authors.initials: F
authors.lastname: Tacchini-Cottier
authors.affiliation: Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Sacks
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics*; D020170:Caspase 1 / Q000235:genetics; D020169:Caspases / Q000235:genetics; D053471:Caspases, Initiator; D004195:Disease Models, Animal; D006801:Humans; D020381:Interleukin-17 / Q000235:genetics; D053583:Interleukin-1beta / Q000235:genetics*; D018320:Leishmania major / Q000276:immunology* / Q000302:isolation & purification; D016773:Leishmaniasis, Cutaneous / Q000276:immunology* / Q000469:parasitology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology*; D012333:RNA, Messenger / Q000096:biosynthesis; D018121:Receptors, Cytokine / Q000235:genetics; D018123:Receptors, Interleukin; D053573:Receptors, Interleukin-1 Type I / Q000235:genetics; D018417:Th1 Cells / Q000276:immunology
chemical_list: D002352:Carrier Proteins; C587672:IL1B protein, mouse; C583355:IL1R1 protein, mouse; C098680:Il17a protein, mouse; C484747:Il27ra protein, mouse; D020381:Interleukin-17; D053583:Interleukin-1beta; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C492716:Nlrp3 protein, mouse; D012333:RNA, Messenger; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D053573:Receptors, Interleukin-1 Type I; C101136:Casp4 protein, mouse; D020169:Caspases; D053471:Caspases, Initiator; D020170:Caspase 1
keywords: IL-1β; Leishmaniasis; Neutrophils; Nlrp3 inflammasome; Skin