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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

Heat map depicting molecules whose expression and phosphorylation level differed when RAW 264.7 cells were treated with nCB compared with PBS or PEG-nCB treated groups detected by reverse phase protein array.DOI:http://dx.doi.org/10.7554/eLife.09623.021
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fig5s1: Heat map depicting molecules whose expression and phosphorylation level differed when RAW 264.7 cells were treated with nCB compared with PBS or PEG-nCB treated groups detected by reverse phase protein array.DOI:http://dx.doi.org/10.7554/eLife.09623.021

Mentions: We conducted additional studies to determine how nCB activates APCs to secrete pro-inflammatory cytokines (e.g., IL-6 and IL-1β) and chemokines. In response to nCB, but not PEG-nCB, reverse phase protein array (RPPA) identified the activation of several DNA damage (e.g., PARP, p-Chk2, p-ATM) and MAPK/Erk (p-ERK, p-MEK1/2)-response proteins (Figure 5A and Figure 5—figure supplement 1). Consistent with these data, we found that nCB, but not PEG-nCB, induced DNA double strand breaks (DSB) as determined by phosphorylation of Histone 2AX (H2AX) on serine 129 (γH2AX) (Figure 5B,C). Further, the induction of DSB was inversely dependent on the size of nCB as we observed progressively fewer DSB with increasing nCB size (Figure 5—figure supplement 2). We next examined whether CB-induced DSB could account for the pro-inflammatory responses seen in APC. Human monocyte-derived dendritic cells (MDDCs) treated with Nu7026, an inhibitor of the DNA-dependent protein kinase catalytic subunit (Wilmore et al., 2004; Zhou et al., 2014), exhibited reduced IL-6 production in a dose-dependent manner in response to nCB but not LPS (Figure 5D). Moreover, in nCB-exposed RAW 264.7 cells, transfection of a specific siRNA against ataxia telangiectasia mutated (ATM)—a serine–threonine kinase that coordinates repair of double-stranded DNA breaks (Guo et al., 2010)—significantly reduced expression of IL-6 and TNFα, two inflammatory cytokines that are induced through ATM (Figure 5—figure supplement 3).10.7554/eLife.09623.020Figure 5.nCB activates APCs by the induction of DNA damage and Erk signaling.


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)

Heat map depicting molecules whose expression and phosphorylation level differed when RAW 264.7 cells were treated with nCB compared with PBS or PEG-nCB treated groups detected by reverse phase protein array.DOI:http://dx.doi.org/10.7554/eLife.09623.021
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4612775&req=5

fig5s1: Heat map depicting molecules whose expression and phosphorylation level differed when RAW 264.7 cells were treated with nCB compared with PBS or PEG-nCB treated groups detected by reverse phase protein array.DOI:http://dx.doi.org/10.7554/eLife.09623.021
Mentions: We conducted additional studies to determine how nCB activates APCs to secrete pro-inflammatory cytokines (e.g., IL-6 and IL-1β) and chemokines. In response to nCB, but not PEG-nCB, reverse phase protein array (RPPA) identified the activation of several DNA damage (e.g., PARP, p-Chk2, p-ATM) and MAPK/Erk (p-ERK, p-MEK1/2)-response proteins (Figure 5A and Figure 5—figure supplement 1). Consistent with these data, we found that nCB, but not PEG-nCB, induced DNA double strand breaks (DSB) as determined by phosphorylation of Histone 2AX (H2AX) on serine 129 (γH2AX) (Figure 5B,C). Further, the induction of DSB was inversely dependent on the size of nCB as we observed progressively fewer DSB with increasing nCB size (Figure 5—figure supplement 2). We next examined whether CB-induced DSB could account for the pro-inflammatory responses seen in APC. Human monocyte-derived dendritic cells (MDDCs) treated with Nu7026, an inhibitor of the DNA-dependent protein kinase catalytic subunit (Wilmore et al., 2004; Zhou et al., 2014), exhibited reduced IL-6 production in a dose-dependent manner in response to nCB but not LPS (Figure 5D). Moreover, in nCB-exposed RAW 264.7 cells, transfection of a specific siRNA against ataxia telangiectasia mutated (ATM)—a serine–threonine kinase that coordinates repair of double-stranded DNA breaks (Guo et al., 2010)—significantly reduced expression of IL-6 and TNFα, two inflammatory cytokines that are induced through ATM (Figure 5—figure supplement 3).10.7554/eLife.09623.020Figure 5.nCB activates APCs by the induction of DNA damage and Erk signaling.

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