Abstract
The interaction of dendritic cells and macrophages with a variety of rigid noncellular particles triggers activation of the NLRP3 inflammasome and consequent secretion of interleukin 1β (IL-1β). Noncellular particles can also be generated in the context of helminth infection, since these large pathogens often shed their outermost structures during growth and/or molting. One such structure is the massive, mucin-based, soft, flexible laminated layer (LL), which protects the larval stages of cestodes of the genus Echinococcus We show that particles from the Echinococcus granulosus LL (pLL) trigger NLRP3- and caspase-1-dependent IL-1β in lipopolysaccharide (LPS)-primed mouse bone marrow-derived dendritic cells (BMDC). This response can be elicited by pLL too large for phagocytosis and nonetheless requires actin dynamics, Syk, and phosphatidylinositol 3-kinase (PI3K). These three requirements had already been observed in our previous study on the alteration by pLL of CD86, CD40, IL-10, and IL-12 responses to LPS in BMDC; 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 our understanding of NLRP3 inflammasome activation by noncellular particulate materials both to helminth-derived materials and to flexible/soft materials.
Keywords:
Echinococcus; NLRP3; PI3K; adjuvants; alum; dendritic cells; exophagy; helminths; inflammation; laminated layer; macrophages; membrane affinity-triggered signaling; mucin.
Copyright © 2020 Casaravilla et al.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Chloromethyl Ketones / pharmacology
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Animals
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Bone Marrow Cells / drug effects
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Bone Marrow Cells / immunology
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Caspase 1 / genetics
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Caspase 1 / immunology
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Cell-Derived Microparticles / chemistry*
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Cell-Derived Microparticles / immunology
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Dendritic Cells / drug effects*
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Dendritic Cells / immunology
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Echinococcus granulosus / chemistry*
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Echinococcus granulosus / immunology
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Female
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Gene Expression Regulation / drug effects*
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Gene Expression Regulation / immunology
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Host-Parasite Interactions / genetics
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Host-Parasite Interactions / immunology*
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Indazoles / pharmacology
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Inflammasomes / drug effects
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Inflammasomes / genetics
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Inflammasomes / immunology
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Interleukin-12 / genetics
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Interleukin-12 / immunology
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Interleukin-1beta / genetics
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Interleukin-1beta / immunology
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Lipopolysaccharides / pharmacology
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Macrophages / drug effects
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Macrophages / immunology
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Mice
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Mice, Inbred C57BL
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NLR Family, Pyrin Domain-Containing 3 Protein / agonists
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NLR Family, Pyrin Domain-Containing 3 Protein / genetics
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NLR Family, Pyrin Domain-Containing 3 Protein / immunology*
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Phagocytosis / drug effects
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Phosphatidylinositol 3-Kinase / genetics
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Phosphatidylinositol 3-Kinase / immunology
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / immunology
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Signal Transduction
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Stilbenes / pharmacology
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Sulfonamides / pharmacology
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Wortmannin / pharmacology
Substances
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2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
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Amino Acid Chloromethyl Ketones
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IL1B protein, mouse
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Indazoles
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Inflammasomes
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Interleukin-1beta
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Lipopolysaccharides
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NLR Family, Pyrin Domain-Containing 3 Protein
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Nlrp3 protein, mouse
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Stilbenes
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Sulfonamides
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benzyloxycarbonyltyrosyl-valyl-alanyl-aspartic acid fluoromethyl ketone
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Interleukin-12
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3,3',4,5'-tetrahydroxystilbene
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Phosphatidylinositol 3-Kinase
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Proto-Oncogene Proteins c-akt
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Casp1 protein, mouse
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Caspase 1
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Wortmannin