Centrality of Myeloid-Lineage Phagocytes in Particle-Triggered Inflammation and Autoimmunity

Our plain-English summary of Centrality of Myeloid-Lineage Phagocytes in Particle-Triggered Inflammation and Autoimmunity, by O.K. Favor, J.J. Pestka, M.A. Bates, et al (Frontiers in Toxicology, 2021).

The study

• Authors: O.K. Favor, J.J. Pestka, M.A. Bates, K.S.S. Lee
• Journal: Frontiers in Toxicology
• Published: 2021;3:777768
• Type of article: Review
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Exposure to exogenous particles found as airborne contaminants or endogenous particles that form by crystallization of certain nutrients can activate inflammatory pathways and potentially accelerate autoimmunity onset and progression in genetically predisposed individuals. The first line of innate immunological defense against particles are myeloid-lineage phagocytes, namely macrophages and neutrophils, which recognize/internalize the particles, release inflammatory mediators, undergo programmed/unprogrammed death, and recruit/activate other leukocytes to clear the particles and resolve inflammation. However, immunogenic cell death and release of damage-associated molecules, collectively referred to as "danger signals," coupled with failure to efficiently clear dead/dying cells, can elicit unresolved inflammation, accumulation of self-antigens, and adaptive leukocyte recruitment/activation. Collectively, these events can promote loss of immunological self-tolerance and onset/progression of autoimmunity. This review discusses critical molecular mechanisms by which exogenous particles (i.e., silica, asbestos, carbon nanotubes, titanium dioxide, aluminum-containing salts) and endogenous particles (i.e., monosodium urate, cholesterol crystals, calcium-containing salts) may promote unresolved inflammation and autoimmunity by inducing toxic responses in myeloid-lineage phagocytes with emphases on inflammasome activation and necrotic and programmed cell death pathways. A prototypical example is occupational exposure to respirable crystalline silica, which is etiologically linked to systemic lupus erythematosus (SLE) and other human autoimmune diseases. Importantly, airway instillation of SLE-prone mice with crystalline silica elicits severe pulmonary pathology involving accumulation of particle-laden alveolar macrophages, dying and dead cells, nuclear and cytoplasmic debris, and neutrophilic inflammation that drive cytokine, chemokine, and interferon-regulated gene expression. Silica-induced immunogenic cell death and danger signal release triggers accumulation of T and B cells, along with IgG-secreting plasma cells, indicative of ectopic lymphoid tissue neogenesis, and broad-spectrum autoantibody production in the lung. These events drive early autoimmunity onset and accelerate end-stage autoimmune glomerulonephritis. Intriguingly, dietary supplementation with ω-3 fatty acids have been demonstrated to be an intervention against silica-triggered murine autoimmunity. Taken together, further insight into how particles drive immunogenic cell death and danger signaling in myeloid-lineage phagocytes and how these responses are influenced by the genome will be essential for identification of novel interventions for preventing and treating inflammatory and autoimmune diseases associated with these agents.

Copyright © 2021 Favor, Pestka, Bates and Lee.

In plain English

This article was a review, not a new study. The authors summarized published research on how outside particles (silica, asbestos, carbon nanotubes, titanium dioxide, aluminum-containing salts) and crystals formed in the body (monosodium urate, cholesterol, calcium salts) affect macrophages and neutrophils, immune cells that engulf particles. They described inflammasome activation and cell death as central mechanisms that may drive inflammation and autoimmunity. The review's tables listed earlier cell studies in which asbestos led to caspase-1 activation and IL-1 beta release in human macrophages, and to necroptosis and NET release in neutrophils. The review also stated that cell receptors for asbestos had not been identified, that asbestos could cause apoptosis in macrophages, and that workplace asbestos inhalation has a long-recorded history of potentiating asbestosis and malignant mesothelioma. The main example was crystalline silica. The authors' laboratory had reported that four weekly intranasal doses of 1 mg triggered glomerulonephritis 12 weeks earlier in lupus-prone female mice, and that dietary DHA worked as a preventive approach. The authors concluded that these mechanisms align with the "danger model." They noted that dose effects on autoimmunity remain largely uninvestigated.

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 laboratory and other studies; no new data collected
• Who was studied: No study population. The review focused on myeloid-lineage phagocytes (macrophages, neutrophils) as described in cell, animal and human studies by others and by the authors' laboratory.
• Exposure: Exogenous particles: silicon dioxide (silica), asbestos, carbon nanotubes, titanium dioxide, aluminum-containing salts. Endogenous particles: monosodium urate, cholesterol crystals, calcium phosphate, calcium oxalate. Asbestos fiber types were not distinguished.
• Main results:
  • The review's Table 2 listed an earlier study (Dostert et al., 2008) in which asbestos at 0.2 mg/ml for 6 hours in THP-1 cells (human macrophages) led to caspase-1 activation and IL-1 beta release
  • Table 2 listed an earlier study (Palomaki et al., 2011) in which asbestos at 100 µg/ml for 6 hours in primary human macrophages led to cathepsin B activity, Syk activity, ROS production and IL-1 beta release
  • Table 2 listed an earlier study (Desai et al., 2017) in which silica and asbestos at 0.2 mg/ml for 2 hours in primary murine and human neutrophils led to NET formation, primary necrosis and necroptosis, and NET release
  • The review stated that surface receptors for asbestos (and for calcium phosphate and calcium oxalate) had not yet been identified
  • Citing earlier studies, the review reported that in macrophages asbestos increased CHOP expression and cytosolic calcium, which the review linked to endoplasmic reticulum stress
  • Citing earlier studies, the review stated that particles including asbestos can induce apoptosis in macrophages
  • The review described the NLRP3 inflammasome as playing a role in particle-driven diseases. It listed pulmonary fibrosis, asthma, COPD, malignant mesothelioma and other lung cancers, citing another review.
  • The review stated that workplace inhalation of asbestos fibers has a long-recorded history of potentiating asbestosis and malignant mesothelioma
  • Citing earlier studies, the review stated that inhaled silica and asbestos bring regulatory T cells to the lungs. These cells secrete TGF-beta and IL-10 and contribute to pulmonary fibrosis.
  • The authors' laboratory had previously reported results in lupus-prone female NZBWF1 mice. Four weekly intranasal instillations of 1 mg of crystalline silica triggered glomerulonephritis 12 weeks earlier than in the conventional model.
  • The authors' laboratory had previously reported that dietary DHA at levels reflecting human intake (2 and 5 g/d) could be used as a preventive approach against silica-triggered autoimmune flaring in NZBWF1 mice
• The authors' conclusion: The authors concluded that the mechanisms by which particles trigger autoimmunity align with Polly Matzinger's danger model. They identified open questions, including how genetics influence the immunotoxic potential of particles.
• Limitations the authors state:
  • The authors stated that the dose-response effects of particle exposure on autoimmune disease remain largely uninvestigated
  • The authors stated that there is currently no evidence linking particle exposure to PANoptosis (combined cell death) in myeloid-lineage phagocytes
  • The authors stated that the links between particles' physical and chemical attributes and toxic responses have not yet been characterized for endogenous particles

Topics

Medical terms in this study, explained in our Lexicon: Inflammation, Macrophage, Occupational Exposure, Crystalline, Pathology, Alveolar Macrophage, Cytokine.

Related studies

• The NLRP3 inflammasome in pathogenic particle and fibre-associated lung inflammation and diseases — M. Sayan, B.T. Mossman (2016)
• TNFalpha and MIP-2: role in particle-induced inflammation and regulation by oxidative stress — K.E. Driscoll (2000)
• The role of sex in particle-induced inflammation and injury — J.L. Ray, P. Fletcher, et al. (2020)
• Apoptosis induced by piroxicam plus cisplatin combined treatment is triggered by p21 in mesothelioma — A. Baldi, M.T. Piccolo, et al. (2011)
• Asbestos-associated neoplasms of B cell lineage — E. Kagan, R.J. Jacobson, et al. (1979)
• 5-hydroxymethylcytosine but not MTAP methylation status can stratify malignant pleural mesothelioma based on the lineage of origin — M. Bosio, E. Salvaterra, et al. (2018)

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