Uncoupling between Inflammatory and Fibrotic Responses to Silica: Evidence from MyD88 Knockout Mice

Re, Sandra Lo; Yakoub, Yousof; Devosse, Raynal; Uwambayinema, Francine; Couillin, Isabelle; Ryffel, Bernard; Marbaix, Étienne; Lison, Dominique; Huaux, François

doi:10.1371/journal.pone.0099383

Cited by 40 publications

(42 citation statements)

References 67 publications

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“…Indeed, we recently showed that mice lacking IL-1β, IL-1α or IL-1R and treated with DQ12 silica presented a reduction of chronic lung inflammation and granuloma formation compared to their WT counterparts. However, this strong effect on inflammatory development was not concomitantly accompanied by a reduction of lung fibrosis, suggesting that inhibiting IL-1-driven inflammation may not be sufficient to control the fibrotic lung disease after particle exposure [ 76 ].…”

Section: Discussionmentioning

confidence: 99%

The alarmin IL-1α is a master cytokine in acute lung inflammation induced by silica micro- and nanoparticles

et al. 2014

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BackgroundInflammasome-activated IL-1β plays a major role in lung neutrophilic inflammation induced by inhaled silica. However, the exact mechanisms that contribute to the initial production of precursor IL-1β (pro-IL-1β) are still unclear. Here, we assessed the implication of alarmins (IL-1α, IL-33 and HMGB1) in the lung response to silica particles and found that IL-1α is a master cytokine that regulates IL-1β expression.MethodsPro- and mature IL-1β as well as alarmins were assessed by ELISA, Western Blot or qRT-PCR in macrophage cultures and in mouse lung following nano- and micrometric silica exposure. Implication of these immune mediators in the establishment of lung inflammatory responses to silica was investigated in knock-out mice or after antibody blockade by evaluating pulmonary neutrophil counts, CXCR2 expression and degree of histological injury.ResultsWe found that the early release of IL-1α and IL-33, but not HMGB1 in alveolar space preceded the lung expression of pro-IL-1β and neutrophilic inflammation in silica-treated mice. In vitro, the production of pro-IL-1β by alveolar macrophages was significantly induced by recombinant IL-1α but not by IL-33. Neutralization or deletion of IL-1α reduced IL-1β production and neutrophil accumulation after silica in mice. Finally, IL-1α released by J774 macrophages after in vitro exposure to a range of micro- and nanoparticles of silica was correlated with the degree of lung inflammation induced in vivo by these particles.ConclusionsWe demonstrated that in response to silica exposure, IL-1α is rapidly released from pre-existing stocks in alveolar macrophages and promotes subsequent lung inflammation through the stimulation of IL-1β production. Moreover, we demonstrated that in vitro IL-1α release from macrophages can be used to predict the acute inflammogenic activity of silica micro- and nanoparticles.Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-014-0069-x) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

The alarmin IL-1α is a master cytokine in acute lung inflammation induced by silica micro- and nanoparticles

et al. 2014

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“…52 Moreover, in a study of the lung inflammatory and fibrotic responses to silica of MyD88 knock-out mice, robust collagen accumulation was observed in knock-out mice in spite of attenuation of lung inflammation, neutrophil accumulation and IL-1β release in response to silica. 62 In that same study, fibrosis was associated with increased levels of pro-fibrotic regulatory T lymphocytes but not with T helper 17 cell influx. 62 The data suggest that the development of lung fibrosis or even other fibrotic diseases appears uncoupled from inflammation and may be orchestrated by a regulatory T lymphocyte-associated pathway.…”

Section: Er Stress Crohn's Disease Intestinal Inflammation and Immumentioning

confidence: 90%

“…62 In that same study, fibrosis was associated with increased levels of pro-fibrotic regulatory T lymphocytes but not with T helper 17 cell influx. 62 The data suggest that the development of lung fibrosis or even other fibrotic diseases appears uncoupled from inflammation and may be orchestrated by a regulatory T lymphocyte-associated pathway. 62 Several ER modulating therapeutic interventions showed that treatment with chemical chaperones improves protein folding in disorders of misfolded proteins, such as alpha-1 antitrypsin deficiency.…”

Section: Er Stress Crohn's Disease Intestinal Inflammation and Immumentioning

confidence: 90%

“…62 The data suggest that the development of lung fibrosis or even other fibrotic diseases appears uncoupled from inflammation and may be orchestrated by a regulatory T lymphocyte-associated pathway. 62 Several ER modulating therapeutic interventions showed that treatment with chemical chaperones improves protein folding in disorders of misfolded proteins, such as alpha-1 antitrypsin deficiency. 63 Agents that ameliorate ER stress by promoting adaptive UPR signaling and/or preventing ER stress-mediated cell apoptosis offer a promising therapy target, such as CHOP inhibitor to reduce inflammation-induced epithelial cell damage.…”

Section: Er Stress Crohn's Disease Intestinal Inflammation and Immumentioning

confidence: 98%

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The Role of Endoplasmic Reticulum Stress in the Development of Fibrosis in Crohn’s Disease

Li¹

2018

Exploratory Research and Hypothesis in Medicine

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When cells are subject to endoplasmic reticulum (ER) stress due to inflammation, inadequate nutrition or infection, a characteristic environment of glucose starvation, acidosis and hypoxia is created. All the conditions cited contribute to ER stress as well as the unfolded protein response (UPR). The UPR is active in a variety of human tumor types. Depending on the severity of ER stress, the UPR can exert a cytoprotective function by resolving the misfolded or unfolded protein, further reducing the ER protein load in mild stress, or by sending signal to cells to undergo cell death by apoptosis in the severe condition. Recent studies suggest that the glucose-regulated protein (GRP)78, or immunoglobulin heavy chain binding protein (BiP), not only confers an advantage to cell survival through an anti-apoptotic function but also may improve cell proliferation and angiogenesis. Understanding how the UPR can induce adaptation to chronic stress instead of apoptosis in cells will be of invaluable significance toward finding a cure for ER stress-associated diseases. This review covers what is known about the adaptive responses of cells when facing ER stress and how these information may lead to discoveries of novel treatments for various related disorders. Studies have suggested that ER stress promotes tissue remodeling under a variety of conditions and through several mechanisms, including activation of apoptosis, epithelialmesenchymal transition, and enhanced inflammatory response. This review also focuses on the major cell components in the gut, primarily epithelial cells and mesenchymal cells, for which a myriad of evidence suggests that sustained ER stress causes epithelial cell damage along with resultant mucosal barrier dysfunction, stimulates mesenchymal cell differentiation, and induces myofibroblasts activation and their secretion of excess extracellular protein leading to matrix collagen-rich tissue formation. Several key questions are still not answered by the fibrosis research and are discussed in this review: for example, the mechanisms of ER stress induction and the specific signaling pathway(s) activated by which UPR leads to development of organ fibrosis, or how to maintain ER stress at a basal level instead of exacerbating its physiological role that is otherwise necessary to maintain intracellular homeostasis. Ultimately, further investigations are needed to bridge the gap between our current understanding of ER stress mechanisms and to identify efficient anti-fibrotic therapeutic regimens.

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“…Interest reports to reveal importance of MyoD88 for lung fibrosis and inflammation caused by silica using MyD88 knockout mice were studied by Re et al [64]. They found that accumulation of Treg and cytokines such as IL-10, TGF-β1, and platelet-derived growth factor (PDGF)-B contributed to lung inflammatory and granuloma responses, whereas this was not with Th17 influx.…”

Section: Effects Of Silica Particles and Asbestos Fibers On Th17mentioning

confidence: 99%

Immune Alteration Caused by Fibrous and Particulate Environmental Substances

Kumagai-Τakei¹,

Lee²,

Yoshitome³

et al. 2020

Environmental Factors Affecting Human Health

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Fibrous and particulate environmental substances such as asbestos fibers and silica particles cause not only lung fibrosis but also various health disturbances. Asbestos induce malignant tumors such as pleural mesothelioma and lung cancer. Silicosis patients exposed to silica particles show complications of various autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, and antineutrophil cytoplasmic antibody (ANCA)-related vasculitis/nephritis. The causative alteration of immune cells exposed to these environmental substances may form baseline modification of human immune system not only localized pulmonary lesions, alteration of alveolar macrophages, and others but also general immune system and changes of function in effector, regulatory, and cytotoxic T cells and natural killer cells. In this review, both (localized and generalized) immune alterations caused by environmental fibrous and particulate substances are summarized and reported.

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Uncoupling between Inflammatory and Fibrotic Responses to Silica: Evidence from MyD88 Knockout Mice

Cited by 40 publications

References 67 publications

The alarmin IL-1α is a master cytokine in acute lung inflammation induced by silica micro- and nanoparticles

The alarmin IL-1α is a master cytokine in acute lung inflammation induced by silica micro- and nanoparticles

The Role of Endoplasmic Reticulum Stress in the Development of Fibrosis in Crohn’s Disease

Immune Alteration Caused by Fibrous and Particulate Environmental Substances

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