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 L. 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 non-healing 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 neutrophils recruitment to the infected skin. Mice deficient in Nlrp3, ASC, and caspase-1/11, or lacking IL-1β or IL-1 receptor signaling, developed healing lesions and cleared LmSd from the site. Resistance to LmSd mice was associated with 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 phenotype 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 non-healing form of cutaneous leishmaniasis in conventionally resistant mice.

Immune responses against protozoan parasites: a focus on the emerging role of Nod-like receptors

“…However, the authors of this study did not find any role for the NLRP3 inflammasome in clearing L. major , suggesting a species-specific role for the NLRP3 inflammasome. The results of a more recent study using a non-healing strain of L. major infection in C57BL/6 mice show that NLRP3 inflammasome–induced IL-1β promotes lesions through recruitment of neutrophils at the site of the infection [100]. Thus, mice deficient in the inflammasome components are significantly less protected from L. major infection in this model system.…”

“…Despite several studies of IL-1 and IL-18, the roles of NLRs (the major regulators of IL-1 cytokine family) during Leishmania infections remain largely unknown. Thus far, only the NLRP3 inflammasome has been shown to be involved in modulating immune responses against Leishmania infections [97–100]. The results of these studies suggest that the NLRP3 inflammasome is directly involved in processing and releasing IL-1β and IL-18 during Leishmania infection in vitro and in vivo (Figure 2b).…”

“…The results of these studies suggest that the NLRP3 inflammasome is directly involved in processing and releasing IL-1β and IL-18 during Leishmania infection in vitro and in vivo (Figure 2b). The NLRP3 inflammasome is similarly required for IL-1β and IL-18 production during L. major infection in both C57BL/6 [98,100] and BALB/c [97] mice. Leishmania -associated metalloprotease GP63 prevents NLRP3 inflammasome activation by inhibiting the production of reactive oxygen species and directly cleaving NLRP3 [99].…”

Cell death offers exceptional cellular and molecular windows for pharmacological interventions in protozoan parasites

“…Recently, L. major Seidman strain (LmSd) -infected C57BL/6 mice has resulted in a non-healing lesion. The most likely causes are the association of NLRP3 inflammasome-dependent IL-1β with localized neutrophil recruitment [120]. Considerably more work will need to be done to expand our current knowledge of inflammasome activation or regulation by protozoan parasites or their components to identify additional host molecules or parasitic protozoan components that activate and manipulate the NLRP3 inflammasome complex.…”

An Anti-Inflammatory Role for NLRP10 in Murine Cutaneous Leishmaniasis

“…NLRP3 inflammasome activation has been implicated in both resistance and susceptibility in murine models of cutaneous leishmaniasis (16–18). However, the role of other NLRs in leishmaniasis is unknown.…”