The Nlrp3 inflammasome,IL‐1β, and neutrophil recruitment are required for susceptibility to a nonhealing strain of Leishmania major in C57BL/6 mice |
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Authors: | Melanie Charmoy Benjamin P. Hurrell Audrey Romano Sang Hun Lee Flavia Ribeiro‐Gomes Nicolas Riteau Katrin Mayer‐Barber Fabienne Tacchini‐Cottier David L. Sacks |
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Affiliation: | 1. Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA;2. Department of Biochemistry, WHO‐Immunology Research and Training Center, University of Lausanne, Lausanne, Switzerland |
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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. |
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Keywords: | IL‐1β Leishmaniasis Nlrp3 inflammasome Neutrophils Skin |
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