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NLRP3 inflammasome activation by mitochondrial ROS in bronchial epithelial cells is required for allergic inflammation.

Kim SR, Kim DI, Kim SH, Lee H, Lee KS, Cho SH, Lee YC - Cell Death Dis (2014)

Bottom Line: Abnormality in mitochondria has been suggested to be associated with development of allergic airway disorders.Finally, blockade of IL-1β substantially reduced airway inflammation and hyperresponsiveness in the asthmatic mice.These findings suggest that mitochondrial ROS have a critical role in the pathogenesis of allergic airway inflammation through the modulation of NLRP3 inflammasome activation, providing a novel role of airway epithelial cells expressing NLRP3 inflammasome as an immune responder.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University - Biomedical Research Institute of Chonbuk National University Hospital, Deokjin-gu, Jeonju, South Korea.

ABSTRACT
Abnormality in mitochondria has been suggested to be associated with development of allergic airway disorders. In this study, to evaluate the relationship between mitochondrial reactive oxygen species (ROS) and NLRP3 inflammasome activation in allergic asthma, we used a newly developed mitochondrial ROS inhibitor, NecroX-5. NecroX-5 reduced the increase of mitochondrial ROS generation in airway inflammatory cells, as well as bronchial epithelial cells, NLRP3 inflammasome activation, the nuclear translocation of nuclear factor-κB, increased expression of various inflammatory mediators and pathophysiological features of allergic asthma in mice. Finally, blockade of IL-1β substantially reduced airway inflammation and hyperresponsiveness in the asthmatic mice. These findings suggest that mitochondrial ROS have a critical role in the pathogenesis of allergic airway inflammation through the modulation of NLRP3 inflammasome activation, providing a novel role of airway epithelial cells expressing NLRP3 inflammasome as an immune responder.

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Related in: MedlinePlus

Effects of blockade of IL-1β on total and differential cell counts in BAL fluids, histological changes and airway hyperresponsiveness in the lung of OVALPS-OVA mice and OVALPS-OVA IL-1R KO mice. All parameters were measured at 48 h after the last challenge in SAL-SAL mice administered with PBS (SP), OVALPS-OVA mice administered with isotype control antibody (OLC-Ab), OVALPS-OVA mice administered with an anti-IL-1β-neutralizing antibody (OLA-IL-1β Ab), SAL-SAL WT mice (WT CON), OVALPS-OVA WT mice (WT OL), SAL-SAL IL-1R KO mice (IL-1R KO CON) and OVALPS-OVA IL-1R KO mice (IL-1R KO OL). (a) Cellular changes in BAL fluids of OVALPS-OVA mice. Bars represent mean±S.E.M. from seven mice per group. (b-d) Representative H&E-stained sections of the lungs isolated from SP (b), OLC-Ab (c) and OLA-IL-1β Ab (d). Bars indicate scale of 20 μm. (e and f) Airway responsiveness in OVALPS-OVA mice was assessed by both noninvasive (e, %Penh) and invasive (f, Rrs) measurements. Bars represent mean±S.E.M. from seven mice per group. (g) Cellular changes in BAL fluids of IL-1R KO or WT mice. Bars represent mean±S.E.M. from five mice per group. (h–k) Representative H&E-stained sections of the lungs isolated from WT CON (h), WT OL (i), IL-1R KO CON (j) and IL-1R KO OL (k). Bars indicate scale of 50 μm. (l) Airway responsiveness in IL-1R KO or WT mice was assessed by invasive measurement (Rrs). Bars represent mean±S.E.M. from five mice per group. #P<0.05 versus SP or WT CON; *P<0.05 versus OLC-Ab or WT OL
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fig7: Effects of blockade of IL-1β on total and differential cell counts in BAL fluids, histological changes and airway hyperresponsiveness in the lung of OVALPS-OVA mice and OVALPS-OVA IL-1R KO mice. All parameters were measured at 48 h after the last challenge in SAL-SAL mice administered with PBS (SP), OVALPS-OVA mice administered with isotype control antibody (OLC-Ab), OVALPS-OVA mice administered with an anti-IL-1β-neutralizing antibody (OLA-IL-1β Ab), SAL-SAL WT mice (WT CON), OVALPS-OVA WT mice (WT OL), SAL-SAL IL-1R KO mice (IL-1R KO CON) and OVALPS-OVA IL-1R KO mice (IL-1R KO OL). (a) Cellular changes in BAL fluids of OVALPS-OVA mice. Bars represent mean±S.E.M. from seven mice per group. (b-d) Representative H&E-stained sections of the lungs isolated from SP (b), OLC-Ab (c) and OLA-IL-1β Ab (d). Bars indicate scale of 20 μm. (e and f) Airway responsiveness in OVALPS-OVA mice was assessed by both noninvasive (e, %Penh) and invasive (f, Rrs) measurements. Bars represent mean±S.E.M. from seven mice per group. (g) Cellular changes in BAL fluids of IL-1R KO or WT mice. Bars represent mean±S.E.M. from five mice per group. (h–k) Representative H&E-stained sections of the lungs isolated from WT CON (h), WT OL (i), IL-1R KO CON (j) and IL-1R KO OL (k). Bars indicate scale of 50 μm. (l) Airway responsiveness in IL-1R KO or WT mice was assessed by invasive measurement (Rrs). Bars represent mean±S.E.M. from five mice per group. #P<0.05 versus SP or WT CON; *P<0.05 versus OLC-Ab or WT OL

Mentions: In order to verify the action mechanism of NecroX-5, that is, whether or not the anti-asthmatic effect of NecroX-5 works via suppression of inflammasome activation, we evaluated the role of IL-1β on changes in BAL cells, histologic features, airway hyperresponsiveness and protein levels of pro-inflammatory cytokines using an anti-IL-1β-neutralizing antibody or IL-1R KO mice. The increased numbers of total cells, lymphocytes, neutrophils and eosinophils in OVALPS-OVA mice were substantially reduced by neutralization of IL-1β with the antibody (Figure 7a). In addition, the OVALPS-OVA mice treated with the anti-IL-1β-neutralizing antibody showed a marked reduction in infiltration of numerous inflammatory cells into peribronchiolar and perivascular regions on histologic examination (Figures 7b–d).


NLRP3 inflammasome activation by mitochondrial ROS in bronchial epithelial cells is required for allergic inflammation.

Kim SR, Kim DI, Kim SH, Lee H, Lee KS, Cho SH, Lee YC - Cell Death Dis (2014)

Effects of blockade of IL-1β on total and differential cell counts in BAL fluids, histological changes and airway hyperresponsiveness in the lung of OVALPS-OVA mice and OVALPS-OVA IL-1R KO mice. All parameters were measured at 48 h after the last challenge in SAL-SAL mice administered with PBS (SP), OVALPS-OVA mice administered with isotype control antibody (OLC-Ab), OVALPS-OVA mice administered with an anti-IL-1β-neutralizing antibody (OLA-IL-1β Ab), SAL-SAL WT mice (WT CON), OVALPS-OVA WT mice (WT OL), SAL-SAL IL-1R KO mice (IL-1R KO CON) and OVALPS-OVA IL-1R KO mice (IL-1R KO OL). (a) Cellular changes in BAL fluids of OVALPS-OVA mice. Bars represent mean±S.E.M. from seven mice per group. (b-d) Representative H&E-stained sections of the lungs isolated from SP (b), OLC-Ab (c) and OLA-IL-1β Ab (d). Bars indicate scale of 20 μm. (e and f) Airway responsiveness in OVALPS-OVA mice was assessed by both noninvasive (e, %Penh) and invasive (f, Rrs) measurements. Bars represent mean±S.E.M. from seven mice per group. (g) Cellular changes in BAL fluids of IL-1R KO or WT mice. Bars represent mean±S.E.M. from five mice per group. (h–k) Representative H&E-stained sections of the lungs isolated from WT CON (h), WT OL (i), IL-1R KO CON (j) and IL-1R KO OL (k). Bars indicate scale of 50 μm. (l) Airway responsiveness in IL-1R KO or WT mice was assessed by invasive measurement (Rrs). Bars represent mean±S.E.M. from five mice per group. #P<0.05 versus SP or WT CON; *P<0.05 versus OLC-Ab or WT OL
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fig7: Effects of blockade of IL-1β on total and differential cell counts in BAL fluids, histological changes and airway hyperresponsiveness in the lung of OVALPS-OVA mice and OVALPS-OVA IL-1R KO mice. All parameters were measured at 48 h after the last challenge in SAL-SAL mice administered with PBS (SP), OVALPS-OVA mice administered with isotype control antibody (OLC-Ab), OVALPS-OVA mice administered with an anti-IL-1β-neutralizing antibody (OLA-IL-1β Ab), SAL-SAL WT mice (WT CON), OVALPS-OVA WT mice (WT OL), SAL-SAL IL-1R KO mice (IL-1R KO CON) and OVALPS-OVA IL-1R KO mice (IL-1R KO OL). (a) Cellular changes in BAL fluids of OVALPS-OVA mice. Bars represent mean±S.E.M. from seven mice per group. (b-d) Representative H&E-stained sections of the lungs isolated from SP (b), OLC-Ab (c) and OLA-IL-1β Ab (d). Bars indicate scale of 20 μm. (e and f) Airway responsiveness in OVALPS-OVA mice was assessed by both noninvasive (e, %Penh) and invasive (f, Rrs) measurements. Bars represent mean±S.E.M. from seven mice per group. (g) Cellular changes in BAL fluids of IL-1R KO or WT mice. Bars represent mean±S.E.M. from five mice per group. (h–k) Representative H&E-stained sections of the lungs isolated from WT CON (h), WT OL (i), IL-1R KO CON (j) and IL-1R KO OL (k). Bars indicate scale of 50 μm. (l) Airway responsiveness in IL-1R KO or WT mice was assessed by invasive measurement (Rrs). Bars represent mean±S.E.M. from five mice per group. #P<0.05 versus SP or WT CON; *P<0.05 versus OLC-Ab or WT OL
Mentions: In order to verify the action mechanism of NecroX-5, that is, whether or not the anti-asthmatic effect of NecroX-5 works via suppression of inflammasome activation, we evaluated the role of IL-1β on changes in BAL cells, histologic features, airway hyperresponsiveness and protein levels of pro-inflammatory cytokines using an anti-IL-1β-neutralizing antibody or IL-1R KO mice. The increased numbers of total cells, lymphocytes, neutrophils and eosinophils in OVALPS-OVA mice were substantially reduced by neutralization of IL-1β with the antibody (Figure 7a). In addition, the OVALPS-OVA mice treated with the anti-IL-1β-neutralizing antibody showed a marked reduction in infiltration of numerous inflammatory cells into peribronchiolar and perivascular regions on histologic examination (Figures 7b–d).

Bottom Line: Abnormality in mitochondria has been suggested to be associated with development of allergic airway disorders.Finally, blockade of IL-1β substantially reduced airway inflammation and hyperresponsiveness in the asthmatic mice.These findings suggest that mitochondrial ROS have a critical role in the pathogenesis of allergic airway inflammation through the modulation of NLRP3 inflammasome activation, providing a novel role of airway epithelial cells expressing NLRP3 inflammasome as an immune responder.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine, Research Center for Pulmonary Disorders, Chonbuk National University Medical School, Research Institute of Clinical Medicine of Chonbuk National University - Biomedical Research Institute of Chonbuk National University Hospital, Deokjin-gu, Jeonju, South Korea.

ABSTRACT
Abnormality in mitochondria has been suggested to be associated with development of allergic airway disorders. In this study, to evaluate the relationship between mitochondrial reactive oxygen species (ROS) and NLRP3 inflammasome activation in allergic asthma, we used a newly developed mitochondrial ROS inhibitor, NecroX-5. NecroX-5 reduced the increase of mitochondrial ROS generation in airway inflammatory cells, as well as bronchial epithelial cells, NLRP3 inflammasome activation, the nuclear translocation of nuclear factor-κB, increased expression of various inflammatory mediators and pathophysiological features of allergic asthma in mice. Finally, blockade of IL-1β substantially reduced airway inflammation and hyperresponsiveness in the asthmatic mice. These findings suggest that mitochondrial ROS have a critical role in the pathogenesis of allergic airway inflammation through the modulation of NLRP3 inflammasome activation, providing a novel role of airway epithelial cells expressing NLRP3 inflammasome as an immune responder.

Show MeSH
Related in: MedlinePlus