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Nanoparticulate carbon black in cigarette smoke induces DNA cleavage and Th17-mediated emphysema.

You R, Lu W, Shan M, Berlin JM, Samuel EL, Marcano DC, Sun Z, Sikkema WK, Yuan X, Song L, Hendrix AY, Tour JM, Corry DB, Kheradmand F - Elife (2015)

Bottom Line: The effect of carbon black (CB), a universal constituent of smoke derived from the incomplete combustion of organic material, in smokers and non-smokers is less known.Increasing the polarity or size of CB mitigated many adverse effects.Thus, nCB causes sterile inflammation, DSB, and emphysema and explains adverse health outcomes seen in smokers while implicating the dangers of nCB exposure in non-smokers.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Baylor College of Medicine, Houston, United States.

ABSTRACT
Chronic inhalation of cigarette smoke is the major cause of sterile inflammation and pulmonary emphysema. The effect of carbon black (CB), a universal constituent of smoke derived from the incomplete combustion of organic material, in smokers and non-smokers is less known. In this study, we show that insoluble nanoparticulate carbon black (nCB) accumulates in human myeloid dendritic cells (mDCs) from emphysematous lung and in CD11c(+) lung antigen presenting cells (APC) of mice exposed to smoke. Likewise, nCB intranasal administration induced emphysema in mouse lungs. Delivered by smoking or intranasally, nCB persisted indefinitely in mouse lung, activated lung APCs, and promoted T helper 17 cell differentiation through double-stranded DNA break (DSB) and ASC-mediated inflammasome assembly in phagocytes. Increasing the polarity or size of CB mitigated many adverse effects. Thus, nCB causes sterile inflammation, DSB, and emphysema and explains adverse health outcomes seen in smokers while implicating the dangers of nCB exposure in non-smokers.

No MeSH data available.


Related in: MedlinePlus

Pycard−/− mice produce less pro-inflammatory chemokines in the lungs in response to nCB challenge.(A) Multiplex detection of indicated chemokines in freshly harvested lung homogenate from different groups of mice. ***p < 0.001, *p < 0.05 as determined by the one-way ANOVA and Bonferroni's multiple comparison test. n = 5 per group. Data are mean ± SEM and representative of two independent studies.DOI:http://dx.doi.org/10.7554/eLife.09623.026
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fig6s1: Pycard−/− mice produce less pro-inflammatory chemokines in the lungs in response to nCB challenge.(A) Multiplex detection of indicated chemokines in freshly harvested lung homogenate from different groups of mice. ***p < 0.001, *p < 0.05 as determined by the one-way ANOVA and Bonferroni's multiple comparison test. n = 5 per group. Data are mean ± SEM and representative of two independent studies.DOI:http://dx.doi.org/10.7554/eLife.09623.026

Mentions: The inflammasome detects danger signals released in response to cell injury and sterile inflammation and the adaptor protein ASC (apoptosis-associated speck-like protein containing CARD) was shown to be required for inflammasome-dependent caspase-1–mediated conversion of pro-IL-1β to mature IL-1β (Kono et al., 2012). In response to nCB exposure, lung CD11c+ mDCs increased IL-6 and IL-1β expression and RAW 264.7 cells released more LDH, consistent with the concept that nCB induces both sterile inflammation and necrotic cell death. To determine if ASC is also required for nCB-induced Th17 responses and emphysema, Pycard−/− mice were challenged intranasally with nCB. When compared to WT mice treated identically, Pycard−/− mice showed attenuated emphysema (Figure 6A–C) and reduced macrophage, neutrophil, lymphocyte, and mDC infiltration into the lungs (Figure 6D,E). Consistently, lung mDCs of Pycard−/− mice produced less IL-6 and IL-1β and poorly activated splenic T cells to differentiate into Th17 cells when compared with WT mDC (Figure 6F–H). Freshly collected lung homogenates from Pycard−/− mice challenged with nCB also showed reduced inflammatory chemokine production compared with WT mice (Figure 6—figure supplement 1). Thus, the earliest immunological events induced by nCB include ASC activation and inflammasome assembly, which are in turn required for nCB-mediated Th17 responses and emphysema.10.7554/eLife.09623.025Figure 6.ASC-mediated inflammasome pathway is required for nCB-induced Th17 responses and emphysema.


Nanoparticulate carbon black in cigarette smoke induces DNA cleavage and Th17-mediated emphysema.

You R, Lu W, Shan M, Berlin JM, Samuel EL, Marcano DC, Sun Z, Sikkema WK, Yuan X, Song L, Hendrix AY, Tour JM, Corry DB, Kheradmand F - Elife (2015)

Pycard−/− mice produce less pro-inflammatory chemokines in the lungs in response to nCB challenge.(A) Multiplex detection of indicated chemokines in freshly harvested lung homogenate from different groups of mice. ***p < 0.001, *p < 0.05 as determined by the one-way ANOVA and Bonferroni's multiple comparison test. n = 5 per group. Data are mean ± SEM and representative of two independent studies.DOI:http://dx.doi.org/10.7554/eLife.09623.026
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4612775&req=5

fig6s1: Pycard−/− mice produce less pro-inflammatory chemokines in the lungs in response to nCB challenge.(A) Multiplex detection of indicated chemokines in freshly harvested lung homogenate from different groups of mice. ***p < 0.001, *p < 0.05 as determined by the one-way ANOVA and Bonferroni's multiple comparison test. n = 5 per group. Data are mean ± SEM and representative of two independent studies.DOI:http://dx.doi.org/10.7554/eLife.09623.026
Mentions: The inflammasome detects danger signals released in response to cell injury and sterile inflammation and the adaptor protein ASC (apoptosis-associated speck-like protein containing CARD) was shown to be required for inflammasome-dependent caspase-1–mediated conversion of pro-IL-1β to mature IL-1β (Kono et al., 2012). In response to nCB exposure, lung CD11c+ mDCs increased IL-6 and IL-1β expression and RAW 264.7 cells released more LDH, consistent with the concept that nCB induces both sterile inflammation and necrotic cell death. To determine if ASC is also required for nCB-induced Th17 responses and emphysema, Pycard−/− mice were challenged intranasally with nCB. When compared to WT mice treated identically, Pycard−/− mice showed attenuated emphysema (Figure 6A–C) and reduced macrophage, neutrophil, lymphocyte, and mDC infiltration into the lungs (Figure 6D,E). Consistently, lung mDCs of Pycard−/− mice produced less IL-6 and IL-1β and poorly activated splenic T cells to differentiate into Th17 cells when compared with WT mDC (Figure 6F–H). Freshly collected lung homogenates from Pycard−/− mice challenged with nCB also showed reduced inflammatory chemokine production compared with WT mice (Figure 6—figure supplement 1). Thus, the earliest immunological events induced by nCB include ASC activation and inflammasome assembly, which are in turn required for nCB-mediated Th17 responses and emphysema.10.7554/eLife.09623.025Figure 6.ASC-mediated inflammasome pathway is required for nCB-induced Th17 responses and emphysema.

Bottom Line: The effect of carbon black (CB), a universal constituent of smoke derived from the incomplete combustion of organic material, in smokers and non-smokers is less known.Increasing the polarity or size of CB mitigated many adverse effects.Thus, nCB causes sterile inflammation, DSB, and emphysema and explains adverse health outcomes seen in smokers while implicating the dangers of nCB exposure in non-smokers.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Baylor College of Medicine, Houston, United States.

ABSTRACT
Chronic inhalation of cigarette smoke is the major cause of sterile inflammation and pulmonary emphysema. The effect of carbon black (CB), a universal constituent of smoke derived from the incomplete combustion of organic material, in smokers and non-smokers is less known. In this study, we show that insoluble nanoparticulate carbon black (nCB) accumulates in human myeloid dendritic cells (mDCs) from emphysematous lung and in CD11c(+) lung antigen presenting cells (APC) of mice exposed to smoke. Likewise, nCB intranasal administration induced emphysema in mouse lungs. Delivered by smoking or intranasally, nCB persisted indefinitely in mouse lung, activated lung APCs, and promoted T helper 17 cell differentiation through double-stranded DNA break (DSB) and ASC-mediated inflammasome assembly in phagocytes. Increasing the polarity or size of CB mitigated many adverse effects. Thus, nCB causes sterile inflammation, DSB, and emphysema and explains adverse health outcomes seen in smokers while implicating the dangers of nCB exposure in non-smokers.

No MeSH data available.


Related in: MedlinePlus