The Nlrp3 inflammasome, IL-1β, and neutrophil recruitment are required for susceptibility to a nonhealing strain of Leishmania major in C57BL/6 mice

Eur J Immunol. 2016 Apr;46(4):897-911. doi: 10.1002/eji.201546015. Epub 2016 Jan 20.


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.

Keywords: IL-1β; Leishmaniasis; Neutrophils; Nlrp3 inflammasome; Skin.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / genetics*
  • Caspase 1 / genetics
  • Caspases / genetics
  • Caspases, Initiator
  • Disease Models, Animal
  • Humans
  • Interleukin-17 / genetics
  • Interleukin-1beta / genetics*
  • Leishmania major / immunology*
  • Leishmania major / isolation & purification
  • Leishmaniasis, Cutaneous / immunology*
  • Leishmaniasis, Cutaneous / parasitology
  • Macrophages / immunology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Neutrophil Infiltration / immunology*
  • Neutrophils / immunology*
  • RNA, Messenger / biosynthesis
  • Receptors, Cytokine / genetics
  • Receptors, Interleukin
  • Receptors, Interleukin-1 Type I / genetics
  • Th1 Cells / immunology


  • Carrier Proteins
  • IL1B protein, mouse
  • IL1R1 protein, mouse
  • Il17a protein, mouse
  • Il27ra protein, mouse
  • Interleukin-17
  • Interleukin-1beta
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Nlrp3 protein, mouse
  • RNA, Messenger
  • Receptors, Cytokine
  • Receptors, Interleukin
  • Receptors, Interleukin-1 Type I
  • Casp4 protein, mouse
  • Caspases
  • Caspases, Initiator
  • Caspase 1