TY - JOUR
T1 - The Effect of PGC-1alpha-SIRT3 Pathway Activation on Pseudomonas aeruginosa Infection
AU - Maurice, Nicholas M.
AU - Bedi, Brahmchetna
AU - Yuan, Zhihong
AU - Lin, Kuo Chuan
AU - Goldberg, Joanna B.
AU - Hart, C. Michael
AU - Bailey, Kristina L.
AU - Sadikot, Ruxana T.
N1 - Funding Information:
Funding: This work was funded by the Department of Veterans Affairs (Merit Review Award 5I01BX001786 to RTS and Veterans Integrated Service Network (VISN) 7 Research Development Award RDA017 to NMM), the National Institutes of Health (R01 HL144478 to RTS) and the Cystic Fibrosis Foundation (CF Foundation Grant to RTS).
Publisher Copyright:
© 2022 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2022/2
Y1 - 2022/2
N2 - The innate immune response to P. aeruginosa pulmonary infections relies on a network of pattern recognition receptors, including intracellular inflammasome complexes, which can recognize both pathogen-and host-derived signals and subsequently promote downstream inflammatory signaling. Current evidence suggests that the inflammasome does not contribute to bacterial clearance and, in fact, that dysregulated inflammasome activation is harmful in acute and chronic P. aeruginosa lung infection. Given the role of mitochondrial damage signals in recruiting inflammasome signaling, we investigated whether mitochondrial-targeted therapies could attenuate inflammasome signaling in response to P. aeruginosa and decrease pathogenicity of infection. In particular, we investigated the small molecule, ZLN005, which transcriptionally activates peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, antioxidant defense, and cellular respiration. We demonstrate that P. aeruginosa infection promotes the expression of inflammasome components and attenuates several components of mitochondrial repair pathways in vitro in lung epithelial cells and in vivo in an acute pneumonia model. ZLN005 activates PGC-1α and its downstream effector, Sirtuin 3 (SIRT3), a mitochondrial-localized deacetylase important for cellular metabolic processes and for reactive oxygen species homeostasis. ZLN005 also attenuates inflammasome signaling induced by P. aeruginosa in bronchial epithelial cells and this action is dependent on ZLN005 activation of SIRT3. ZLN005 treatment reduces epithelial-barrier dysfunction caused by P. aeruginosa and decreases pathogenicity in an in vivo pneumonia model. Therapies that activate the PGC-1α—SIRT3 axis may provide a complementary approach in the treatment of P. aeruginosa infection.
AB - The innate immune response to P. aeruginosa pulmonary infections relies on a network of pattern recognition receptors, including intracellular inflammasome complexes, which can recognize both pathogen-and host-derived signals and subsequently promote downstream inflammatory signaling. Current evidence suggests that the inflammasome does not contribute to bacterial clearance and, in fact, that dysregulated inflammasome activation is harmful in acute and chronic P. aeruginosa lung infection. Given the role of mitochondrial damage signals in recruiting inflammasome signaling, we investigated whether mitochondrial-targeted therapies could attenuate inflammasome signaling in response to P. aeruginosa and decrease pathogenicity of infection. In particular, we investigated the small molecule, ZLN005, which transcriptionally activates peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis, antioxidant defense, and cellular respiration. We demonstrate that P. aeruginosa infection promotes the expression of inflammasome components and attenuates several components of mitochondrial repair pathways in vitro in lung epithelial cells and in vivo in an acute pneumonia model. ZLN005 activates PGC-1α and its downstream effector, Sirtuin 3 (SIRT3), a mitochondrial-localized deacetylase important for cellular metabolic processes and for reactive oxygen species homeostasis. ZLN005 also attenuates inflammasome signaling induced by P. aeruginosa in bronchial epithelial cells and this action is dependent on ZLN005 activation of SIRT3. ZLN005 treatment reduces epithelial-barrier dysfunction caused by P. aeruginosa and decreases pathogenicity in an in vivo pneumonia model. Therapies that activate the PGC-1α—SIRT3 axis may provide a complementary approach in the treatment of P. aeruginosa infection.
KW - Inflammasome
KW - P. aeruginosa
KW - Peroxisome proliferator-activated receptor-γ coactivator-1α
KW - SIRT3
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U2 - 10.3390/pathogens11020116
DO - 10.3390/pathogens11020116
M3 - Article
C2 - 35215060
AN - SCOPUS:85123233154
SN - 2076-0817
VL - 11
JO - Pathogens
JF - Pathogens
IS - 2
M1 - 116
ER -