The microbial and danger signals that activate Nod-like receptors

Our plain-English summary of The microbial and danger signals that activate Nod-like receptors, by S. Benko, D.J. Philpott, S.E. Girardin (Cytokine, 2008).

The study

• Authors: S. Benko, D.J. Philpott, S.E. Girardin
• Journal: Cytokine
• Published: 2008;43(3):368-73
• Type of article: Review
• Cited by: 116 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Nod-like receptors (NLRs) are a family of intracellular sensors that play key roles in innate immunity and inflammation. While some NLRs, including Nod1, Nod2, NAIP and IPAF, detect conserved bacterial molecular signatures from within the host cytosol, other members of this family seem to have evolved the capacity to sense danger signals perhaps independently of a microbial trigger. This is illustrated by the discovery that Nalp3 and Nalp1 are specifically activated by low concentrations of intracellular potassium. The fact that several stimuli, including bacterial toxins and some viruses, but also sterile crystals made of uric acid, asbestos or aluminium hydroxide, can trigger the Nalp3 inflammasome illustrate the fascinating prospect that microbial infections and certain danger signals may be perceived similarly by host recognition systems. Gaining insight into the function of NLR proteins in general will impact considerably on our understanding of the mechanisms underlying immunity to infection, adjuvanticity and auto-inflammatory disorders. In this review, we summarize the current knowledge on the microbial- and danger-derived signals that activate NLRs.

In plain English

This article was a short review (a "minireview"), not a new study. It summarized published laboratory research on Nod-like receptors (NLRs), a family of sensor proteins inside cells that help start inflammation. The review described how two NLRs, Nod1 and Nod2, recognize fragments of bacterial cell walls, and how another, IPAF, recognizes flagellin, a bacterial protein. It described a fourth NLR, Nalp3, as switched on by many kinds of triggers: products of viruses or bacteria, substances released during stress or danger, and foreign particles. Among these, the review cited a 2008 study by other researchers (Dostert and colleagues) reporting that asbestos and silica induced production of the inflammatory signal IL-1 beta in human macrophages, a type of immune cell. The review named no asbestos fiber types and gave no new data on asbestos. The authors concluded that, from the body's point of view, danger signals and microbial signals appear closely linked. They noted that proof of a common trigger awaits further research, and that most NLRs still have no known trigger.

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 minireview of published laboratory research; no original data
• Who was studied: No people or animals were studied. The review covered published research on Nod-like receptors, a family of sensor proteins inside cells, including Nod1, Nod2, IPAF, NAIP, Nalp1 and Nalp3.
• Exposure: Microbial triggers (bacterial cell-wall fragments, flagellin, bacterial toxins, viruses) and non-microbial triggers, including asbestos and silica, uric acid crystals, chemicals and alum adjuvants. No asbestos fiber type, product or dose was specified.
• Main results:
  • From the studies reviewed: Nod2 recognizes muramyl dipeptide, the smallest structure shared by all bacterial peptidoglycans (cell-wall material).
  • From the studies reviewed: the bacterial protein flagellin is detected outside cells by TLR5 and inside cells by the NLR protein IPAF.
  • The review grouped the compounds reported to activate the Nalp3 inflammasome into three classes: products of viruses or bacteria, end- or by-products of danger or stress signals, and foreign (xenogenous) particles.
  • The review cited another group's study (reference 59, Dostert and colleagues, 2008) reporting that asbestos and silica induced IL-1 beta production in human macrophages. That study suggested this may happen through reactive oxygen species generated when the cells fail to fully engulf the particles ("frustrated phagocytosis").
  • From the studies reviewed: uric acid crystals (gout) and calcium pyrophosphate dihydrate crystals (pseudogout) stimulate the Nalp3 inflammasome to produce active IL-1 beta in macrophages.
  • From the studies reviewed: alum adjuvants used in human vaccines lead to Nalp3 inflammasome activation.
• The authors' conclusion: The authors concluded that the recent identification of microbial and non-microbial (aseptic) signals that trigger NLRs illustrates that, from the host's point of view, danger signals and microbial signals are closely linked. They described a future challenge as understanding how the host responds differently to microbes, danger signals and foreign compounds.
• Limitations the authors state:
  • The authors stated that the idea of a common trigger for Nalp3 (such as low potassium inside the cell, or reactive oxygen species) still lacks biochemical and molecular proof, and that how such changes are sensed awaits further research.
  • The authors stated that the NLR family has more than 20 members, but activating triggers have been reported for only a few of them.
  • The authors stated that the detailed molecular mechanism by which alum activates Nalp3 is not yet known.
  • The authors stated that the role of pannexin-1 in inflammasome activation is still unclear.

Topics

Medical terms in this study, explained in our Lexicon: Inflammation, Discovery.

Related studies

• Genes involved in innate immunity associated with asbestos-related fibrotic changes — M.K. Kukkonen, T. Vehmas, et al. (2014)
• Long, needle-like carbon nanotubes and asbestos activate the NLRP3 inflammasome through a similar mechanism — J. Palomäki, E. Välimäki, et al. (2011)
• Nanoparticles activate the NLR pyrin domain containing 3 (Nlrp3) inflammasome and cause pulmonary inflammation through release of IL-1α and IL-1β — A.S. Yazdi, G. Guarda, et al. (2010)
• A genetic variant of NLRP1 gene is associated with asbestos body burden in patients with malignant pleural mesothelioma — S. Crovella, R.R. Moura, et al. (2018)
• High-temperature calcined fullerene nanowhiskers as well as long needle-like multi-wall carbon nanotubes have abilities to induce NLRP3-mediated IL-1β secretion — H. Cui, W. Wu, et al. (2014)
• The Nalp3 inflammasome is essential for the development of silicosis — S.L. Cassel, S.C. Eisenbarth, et al. (2008)

Browse more research in Cytokine, or return to medical research.