Canonical stimulation of the NLRP3 inflammasome by fungal antigens links innate and adaptive B-lymphocyte responses by modulating IL-1β and IgM production

Mohamed F. Ali, Harika Dasari, Virginia P. Van Keulen, Eva M Carmona Porquera

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Article number1504
JournalFrontiers in Immunology
Volume8
Issue numberNOV
DOIs
StatePublished - Nov 9 2017

Fingerprint

Fungal Antigens
Inflammasomes
Interleukin-1
Immunoglobulin M
B-Lymphocytes
Glucans
Caspase 1
Sirolimus
Lymphocyte Activation
Antibodies
Fungal DNA
Pneumocystis
Pattern Recognition Receptors
Antigens
Bacterial DNA
B-Lymphoid Precursor Cells
Mycoses
Transcription Factor AP-1
Infection
Cell Wall

Keywords

  • B-lymphocytes
  • beta;-glucan
  • CpG
  • Fungi
  • IgM
  • IL-1beta;
  • Inflammasome
  • NLRP3

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Canonical stimulation of the NLRP3 inflammasome by fungal antigens links innate and adaptive B-lymphocyte responses by modulating IL-1β and IgM production. / Ali, Mohamed F.; Dasari, Harika; Van Keulen, Virginia P.; Carmona Porquera, Eva M.

In: Frontiers in Immunology, Vol. 8, No. NOV, 1504, 09.11.2017.

Research output: Contribution to journalArticle

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