Abstract
The NLRP3 inflammasome is activated in response to different bacterial, viral, and fungal pathogens and serves as modulator of different pattern recognition receptors signaling pathways. One of the main functions of NLRP3 is to participate in IL-1β maturation which is important in the host defense against Pneumocystis and other fungal infections. However, dysregulation of NLRP3 and IL-1β secretion are also implicated in the pathophysiology of many auto-inflammatory disorders. Often time’s inflammatory flares are preceded by infectious illnesses questioning the role of infection in autoimmune exacerbations. However, we still do not fully understand the exact role that infection or even colonization plays as a trigger of inflammation. Herein, we investigated the role of NLRP3 in circulating B-lymphocytes following activation with two major microbial antigens (β-glucan and CpG). NLRP3 was determined essential in two independent B-lymphocytes processes: pro-inflammatory cytokine secretion and antibody regulation. Our results show that the β-glucan fungal cell wall carbohydrate stimulated B-lymphocytes to secrete IL-1β in a process partially mediated by Dectin-1 activation via SYK and the transcription factors NF-κB and AP-1. This IL-1β secretion was regulated by the NLRP3 inflammasome and was dependent on potassium efflux and Caspase-1. Interestingly, B-lymphocytes activated by unmethylated CpG motifs, found in bacterial and fungal DNA, failed to induce IL-1β. However, B-lymphocyte stimulation by CpG resulted in NLRP3 and Caspase-1 activation and the production and secretion of IgM antibodies. Furthermore, CpG-stimulated IgM secretion, unlike β-glucan-mediated IL-1β production, was mediated by the mammalian target of rapamycin (mTOR). Inhibition of NLRP3 and the mTOR pathway in CpG activated B-lymphocytes resulted in impaired IgM secretion suggesting their participation in antibody regulation. In conclusion, this study describes a differential response of NLRP3 to β-glucan and CpG antigens and identifies the NLRP3 inflammasome of human circulating B-lymphocytes as a modulator of the innate and adaptive immune systems.
Highlights
The host immune system greatly determines the severity of fun gal diseases
Our published studies demonstrated that β-glucaninduced IL-8 secretion had no effect on IgM while CpG stimulated IgM secretion did not participate in IL-8 secretion [7]
We demonstrate that in human peripheral B-lymphocytes the NLRP3 inflammasome is differentially acti vated by fungal β-glucan and CpG antigens
Summary
The host immune system greatly determines the severity of fun gal diseases. In patients with an intact immune system, fungal infections are often clinically asymptomatic or manifest as a mild respiratory illness. B-lymphocytes, well-known players of the adaptive immune response, react to fungal pathogens by generating antibodies and by releasing inflammatory cytokines [1, 2]. T-cell independent activation of B-lymphocytes results in the release of a variety of cytokines and chemokines which are mostly triggered by the activation of pattern recognition receptors (PRRs) such as toll-like recep tors (TLRs) and C-lectin receptors [3]. B-lymphocyte activation by β-glucan and CpG results in the secretion of a specific profile of pro-inflammatory cytokines and chemokines important for the orchestration and activation of monocytes, macrophages, and neutrophils and essential for host defense against fungal and other infections [6,7,8]
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