Inflammasome-Independent Role for NLRP3 in Controlling Innate Antihelminth Immunity and Tissue Repair in the Lung

Chenery, Alistair; Alhallaf, Rafid; Khudhair, Zainab; Ajendra, Jesuthas; Parkinson, JE; Cooper, Martha M; Chan, Brian H. K.; Eichenberger, Ramon M.; Dent, Lindsay A.; Robertson, Avril A. B.; Kupz, Andreas; Brough, David; Loukas, Alex; Sutherland, Tara E.; Allen, Judith E.; Giacomin, Paul

doi:10.4049/jimmunol.1900640

Cited by 24 publications

(18 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These data suggest that NLRP3 has differential roles in innate immunity and reproduction. Our data are consistent with previous reports showing the preventive role of NLRP3 deletion, but not caspase-1/11 or ASC in other tissues and pathologies (22,23).…”

Section: Discussionsupporting

confidence: 94%

Inhibition of the NLRP3 inflammasome prevents ovarian aging

Navarro‐Pando

Alcocer-Gómez

Castejón-Vega

et al. 2020

Preprint

View full text Add to dashboard Cite

Inflammation is a hallmark of many processes during aging and reproductive physiology, negatively affecting female fertility. The goal of this study was to evaluate the role of the NLRP3 inflammasome in ovarian aging and female fertility. Age-dependent increased expression of NLRP3 in the ovary was observed in female WT mice during reproductive aging. High expression of NLRP3, caspase 1 and IL-1β was also observed in granulosa cells from patients with primary ovarian insufficiency. Ablation of the NLRP3 inflammasome improved the survival and pregnancy rates in mice, increased hormonal levels of AMH, a biochemical marker of ovarian reserve, and autophagy rates in ovarian tissue. Deficiency of the NLRP3 inflammasome also reduced serum FSH and estradiol levels. Consistent with these results, pharmacological inhibition of NLRP3 using a direct NLRP3 inhibitor, MCC950, improved fertility in female mice to levels comparable to those of Nlrp3−/− mice. These results suggest that the NLRP3 inflammasome is implicated in the age-dependent loss of female fertility and position this inflammasome as a potential new therapeutic target for the treatment of infertility.

show abstract

Section: Discussionsupporting

confidence: 94%

Inhibition of the NLRP3 inflammasome prevents ovarian aging

Navarro‐Pando

Alcocer-Gómez

Castejón-Vega

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Compared with our findings, two recent reports showed that NLRP3 suppresses innate and adaptive Th2 immune responses in a model of helminth infection ( 33 , 34 ). This finding suggests that NLRP3 displays different functions depending on different factors, such as the insult, microenvironment, cell or tissue type, and cell activation or differentiation status.…”

Section: Discussioncontrasting

confidence: 85%

NLRP3 Regulates IL-4 Expression in TOX+ CD4+ T Cells of Cutaneous T Cell Lymphoma to Potentially Promote Disease Progression

et al. 2021

View full text Add to dashboard Cite

In cutaneous T cell lymphoma (CTCL), a dominant Th2 profile associated with disease progression has been proposed. Moreover, although the production and regulation of IL-4 expression during the early stages of the disease may have important implications in later stages, these processes are poorly understood. Here, we demonstrate the presence of TOX+ CD4+ T cells that produce IL-4+ in early-stage skin lesions of CTCL patients and reveal a complex mechanism by which the NLRP3 receptor promotes a Th2 response by controlling IL-4 production. Unassembled NLRP3 is able to translocate to the nucleus of malignant CD4+ T cells, where it binds to the human il-4 promoter. Accordingly, IL-4 expression is decreased by knocking down and increased by promoting the nuclear localization of NLRP3. We describe a positive feedback loop in which IL-4 inhibits NLRP3 inflammasome assembly, thereby further increasing its production. IL-4 induced a potentially malignant phenotype measured based on TOX expression and proliferation. This mechanism of IL-4 regulation mediated by NLRP3 is amplified in late-stage CTCL associated with disease progression. These results indicate that NLRP3 might be a key regulator of IL-4 expression in TOX+ CD4+ T cells of CTCL patients and that this mechanism might have important implications in the progression of the disease.

show abstract

“…Recent work suggests that it plays important roles in helminth infections, antagonizing type 2 responses and potentiating Th17/inflammatory responses, with impacts on parasite burden and pathology ( 3 – 8 ). In addition, and counterintuitively, NLRP3 can promote type 2 responses, independently of the inflammasome ( 9 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

Activation of the NLRP3 Inflammasome by Particles from the Echinococcus granulosus Laminated Layer

et al. 2020

Self Cite

View full text Add to dashboard Cite

The interaction of dendritic cells and macrophages with a variety of rigid non-cellular particles triggers activation of the NLRP3 inflammasome and consequent secretion of IL-1β. Non-cellular particles can also be generated in the context of helminth infection, as these large pathogens often shed their outermost structures during growth and/or moulting. One such structure is the massive, mucin-based, soft and flexible laminated layer (LL), which protects the larval stages of cestodes of the genus Echinococcus. We show that particles from the E. granulosus LL (pLL) trigger NLRP3- and caspase-1-dependent IL-1β in LPS-primed mouse bone marrow-derived dendritic cells (BMDC). This response can be elicited by pLL particles too large for phagocytosis, and nonetheless requires actin dynamics, Syk and PI3K. These three requirements had already been observed in our previous study on the alteration by pLL of BMDC responses to LPS in terms of CD86, CD40, IL-10 and IL-12: however, we now show that these alterations are independent of NLRP3 and caspase-1. In other words, an initial interaction with particles requiring actin dynamics, Syk and PI3K but not phagocytosis elicits both NLRP3-dependent and NLRP3-independent responses. Intraperitoneal injection of pLL induced IL-1β, suggesting that contact with LL materials induces IL-1β in the E. granulosus infection setting. Our results extend NLRP3 inflammasome activation by non-cellular particulate materials both to helminth-derived and to flexible/soft materials.

show abstract

Inflammasome-Independent Role for NLRP3 in Controlling Innate Antihelminth Immunity and Tissue Repair in the Lung

Cited by 24 publications

References 45 publications

Inhibition of the NLRP3 inflammasome prevents ovarian aging

Inhibition of the NLRP3 inflammasome prevents ovarian aging

NLRP3 Regulates IL-4 Expression in TOX+ CD4+ T Cells of Cutaneous T Cell Lymphoma to Potentially Promote Disease Progression

Activation of the NLRP3 Inflammasome by Particles from the Echinococcus granulosus Laminated Layer

Contact Info

Product

Resources

About