Inflammasome activation and Th17 responses

Our plain-English summary of Inflammasome activation and Th17 responses, by J. Deng, X.Q. Yu, P.H. Wang (Molecular Immunology, 2019).

The study

• Authors: J. Deng, X.Q. Yu, P.H. Wang
• Journal: Molecular Immunology
• Published: 2019;107:142-164
• Type of article: Review
• Cited by: 81 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Immune sensing of exogenous molecules from microbes (e.g., pathogen-associated molecular patterns) and nonmicrobial molecules (e.g., asbestos, alum, and silica), as well as endogenous damage-associated molecular patterns (e.g., ATP, uric acid crystals, and amyloid A) activates innate immunity by inducing immune-related genes, including proinflammatory cytokines, which further facilitate the development of adaptive immunity. The roles of transcriptional responses downstream of immune sensing have been widely characterized in informing adaptive immunity; however, few studies focus on the effect of post-translational responses on the modulation of adaptive immune responses. Inflammasomes activated by the previously described endo- and exogenous stimuli autocatalytically induce intracellular pro-caspase-1, which cleaves the inactive precursors of interleukin-1β (IL-1β) and IL-18 into bioactive proinflammatory cytokines. IL-1β and IL-18 not only contribute to the host defense against infections by activating phagocytes, such as monocytes, macrophages, dendritic cells, and neutrophils, but also induce T-helper 17 (Th17)- and Th1-mediated adaptive immune responses. In synergy with IL-6 and IL-23, IL-1β activates IL-1 receptor (IL-1R) signaling to drive the differentiation of IL-17-producing Th17 cells, which not only play critical roles in host protective immunity to infections of bacteria, fungi, and certain viruses but also participate in the pathology of inflammatory disorders and tumorigenesis. Consequently, targeting inflammasomes and IL-1/IL-1R signaling may effectively improve the treatment of Th17-associated disorders, such as autoinflammatory diseases and cancers, thereby providing novel insights into drug development.

Copyright © 2019 Elsevier Ltd. All rights reserved.

In plain English

This article is a narrative review, not a new study. The authors summarized published laboratory, animal and patient research on inflammasomes, protein complexes inside immune cells that release the inflammatory signals IL-1β and IL-18. They also covered how IL-1β helps produce Th17 cells, a type of immune cell that makes IL-17. Asbestos appears only in passing. Citing earlier work, the authors listed asbestos, along with silica and alum, among particles from the outside environment that can activate the NLRP3 inflammasome. They described a proposed mechanism in which silica and asbestos crystals damage lysosomes, small compartments inside cells. They also cited a report that variants of a related gene, NLRP1, are associated with asbestos-associated mesothelioma. The review did not name fiber types or report any exposure measurements. Most of the article covered infections, autoimmune diseases and cancer. For cancer, the reviewed studies described IL-1β released during chemotherapy as having both pro- and anti-tumor effects, depending on context; some tumor-promoting effects acted through Th17 cells. The authors concluded that targeting this pathway may offer new treatment strategies, and noted that many mechanisms remain unclear.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Narrative review of published research on inflammasome activation and Th17 responses; no original data
• Who was studied: No study population of its own; the review drew on published cell, animal (mostly mouse) and patient studies. No search method or number of reviewed studies is reported.
• Exposure: Asbestos is mentioned only as one of several environmental particles (with silica and alum) that activate the NLRP3 inflammasome; no fiber types, products, jobs or doses are given
• Main results:
  • Citing earlier work, the review described a proposed 'lysosomal disruption' mechanism of NLRP3 activation that includes environmental crystals such as silica and asbestos (attributed to Dostert et al., 2008)
  • The review cited a report (Yu et al., 2018) that NLRP1 gene variants are associated with cancers including asbestos-associated mesothelioma
  • The authors described an inflammasome to IL-1/IL-1 receptor to Th17 pathway in the immune response, based on the studies reviewed
  • Based on the reviewed studies, inflammasome-driven IL-1β during chemotherapy was described as having both pro-tumor and anti-tumor effects, depending on context
  • The review described IL-1β-induced Th17 cells as promoting tumor growth through IL-17 secretion in some settings
• The authors' conclusion: The authors concluded that targeting the inflammasome, IL-1/IL-1 receptor and Th17 pathway may provide new strategies for therapy and disease control
• Limitations the authors state:
  • The authors stated that not all relevant studies could be discussed because of space limits
  • The authors stated that there is no unified mechanism or common model for how NLRP3 is activated

Topics

Medical terms in this study, explained in our Lexicon: Cytokine, Macrophage, Pathology, Tumorigenesis.

Related studies

• The role of inflammasome-derived IL-1 in driving IL-17 responses — K.H. Mills, L.S. Dungan, et al. (2013)
• Inflammasome inhibition under physiological and pharmacological conditions — E.A. Caseley, J.A. Poulter, et al. (2020)
• Transcriptional activation of inflammasome components by Libby amphibole and the role of iron — J.H. Shannahan, A.J. Ghio, et al. (2012)
• Differential activation of the inflammasome in THP-1 cells exposed to chrysotile asbestos and Libby "six-mix" amphiboles and subsequent activation of BEAS-2B cells — M. Li, M.E. Gunter, et al. (2012)
• Vimentin regulates activation of the NLRP3 inflammasome — G. dos Santos, M.R. Rogel, et al. (2015)
• Double-walled carbon nanotubes trigger IL-1β release in human monocytes through Nlrp3 inflammasome activation — E. Meunier, A. Coste, et al. (2012)

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