Limits...
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

Inhibition of DNA damage does not affect Th1 or Th2 responses.IFN-γ (A) and IL-4 (B) concentrations were measured using ELISA in the supernatant of anti-CD3 (1 μg/ml) treated CD4+ T cells co-cultured with lung CD11c+ cell isolated from the mice challenged with PBS or nCB in the presence of vehicle (DMSO) or inhibitors of DNA damage (Nu7026 or Ku55933 at 100 nM). n = 5 per group, and data are mean ± SEM.DOI:http://dx.doi.org/10.7554/eLife.09623.024
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4612775&req=5

fig5s4: Inhibition of DNA damage does not affect Th1 or Th2 responses.IFN-γ (A) and IL-4 (B) concentrations were measured using ELISA in the supernatant of anti-CD3 (1 μg/ml) treated CD4+ T cells co-cultured with lung CD11c+ cell isolated from the mice challenged with PBS or nCB in the presence of vehicle (DMSO) or inhibitors of DNA damage (Nu7026 or Ku55933 at 100 nM). n = 5 per group, and data are mean ± SEM.DOI:http://dx.doi.org/10.7554/eLife.09623.024

Mentions: To further examine whether induction of Th17 responses is dependent on nCB-mediated DNA damage, CD11c+ lung mDCs isolated from nCB-challenged mice were co-cultured with splenic CD4 T cells in the presence of either Nu7026 or Ku55933, an inhibitor of ATM (Li and Yang, 2010), for 3 days. As expected, mDCs isolated from nCB-challenged mice promoted Th17 cell differentiation, which was significantly reduced in response to Nu7026 or Ku55933 (Figure 5E) while Th1 and Th2 cell differentiation remained unchanged (Figure 5—figure supplement 4). Together, these findings suggest that nCB-mediated DNA damage is required for the induction of pro-inflammatory cytokines in mDCs and Th17 cell differentiation. Moreover, nCB exposure in a dose- and time-dependent way increased phosphorylation of Erk (Figure 5F), and similar inhibition of MEK1/2 with U0126, an inhibitor of MAP kinases (Newton et al., 2000), reduced IL-6 production in response to nCB exposure (Figure 5G). Together, these findings indicate that hydrophobic nCB activates DNA damage responses and induces MAPK/Erk signaling coincident with the induction of Th17 responses.


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)

Inhibition of DNA damage does not affect Th1 or Th2 responses.IFN-γ (A) and IL-4 (B) concentrations were measured using ELISA in the supernatant of anti-CD3 (1 μg/ml) treated CD4+ T cells co-cultured with lung CD11c+ cell isolated from the mice challenged with PBS or nCB in the presence of vehicle (DMSO) or inhibitors of DNA damage (Nu7026 or Ku55933 at 100 nM). n = 5 per group, and data are mean ± SEM.DOI:http://dx.doi.org/10.7554/eLife.09623.024
© Copyright Policy
Related In: Results  -  Collection

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

fig5s4: Inhibition of DNA damage does not affect Th1 or Th2 responses.IFN-γ (A) and IL-4 (B) concentrations were measured using ELISA in the supernatant of anti-CD3 (1 μg/ml) treated CD4+ T cells co-cultured with lung CD11c+ cell isolated from the mice challenged with PBS or nCB in the presence of vehicle (DMSO) or inhibitors of DNA damage (Nu7026 or Ku55933 at 100 nM). n = 5 per group, and data are mean ± SEM.DOI:http://dx.doi.org/10.7554/eLife.09623.024
Mentions: To further examine whether induction of Th17 responses is dependent on nCB-mediated DNA damage, CD11c+ lung mDCs isolated from nCB-challenged mice were co-cultured with splenic CD4 T cells in the presence of either Nu7026 or Ku55933, an inhibitor of ATM (Li and Yang, 2010), for 3 days. As expected, mDCs isolated from nCB-challenged mice promoted Th17 cell differentiation, which was significantly reduced in response to Nu7026 or Ku55933 (Figure 5E) while Th1 and Th2 cell differentiation remained unchanged (Figure 5—figure supplement 4). Together, these findings suggest that nCB-mediated DNA damage is required for the induction of pro-inflammatory cytokines in mDCs and Th17 cell differentiation. Moreover, nCB exposure in a dose- and time-dependent way increased phosphorylation of Erk (Figure 5F), and similar inhibition of MEK1/2 with U0126, an inhibitor of MAP kinases (Newton et al., 2000), reduced IL-6 production in response to nCB exposure (Figure 5G). Together, these findings indicate that hydrophobic nCB activates DNA damage responses and induces MAPK/Erk signaling coincident with the induction of Th17 responses.

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