Canonical Stimulation of the NLRP3 Inflammasome by Fungal Antigens Links Innate and Adaptive B-Lymphocyte Responses by Modulating IL-1β and IgM Production

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.

Inflammasome activation and regulation: toward a better understanding of complex mechanisms

“…NLRP9b, mainly expressed in intestinal epithelial cells (IECs), is capable of recognizing the short double-stranded RNA of rotavirus through host RNA helicase Dhx9 33 . Major fungal PAMPs such as β-glucan upon Aspergillus fumigatus infection 34 , fungal CPG 35 , Candidalysin secreted by Candida albicans 36,37 are direct inducers of inflammasome assembly, mainly for the NLRP3 inflammasome. Moreover, activation of both canonical and noncanonical inflammasomes (mainly involving mouse caspase-11 or human caspase-4/5) by diverse parasitic stimuli, such as Leishmania and its lipophosphoglycan 38,39 and Fasciola hepatica-derived molecule cathepsin L3 40 have recently been discovered as an important strategy for the restriction and control of parasitic invasion.…”

The Multifaceted B Cell Response to Influenza Virus

“…Specifically, the activation of TLR7 on murine B cells has been shown to induce IFN-a production during influenza, although not to EBV infection (92,93). B cells also express inflammasome complexes (94) and thus can promote Caspase-1-mediated processing of the inflammatory cytokines IL-1, IL-18, and IL-33 into their active forms (95). IL-1b is particularly interesting as IL-1 knockout mice showed increased morbidity and mortality following influenza infection, which correlated with decreases in amounts of serum and airway influenza-binding IgM (96).…”

Activation of Interleukin-1β Release by the Classical Swine Fever Virus Is Dependent on the NLRP3 Inflammasome, Which Affects Virus Growth in Monocytes

“…NLRP3 has been widely shown to be activated during infections with pathogenic microbes by interleukin-1β (IL-1β) (Ali et al, 2017 ). IL-1β, which is a key cytokine, is associated with both acute and chronic inflammation and with viral disease (Negash et al, 2013 ).…”