Critical Role of SerpinB1 in Regulating Inflammatory Responses in Pulmonary Influenza Infection

Gong, Dapeng; Farley, Kalamo; White, Mitchell R.; Hartshorn, Kevan L.; Benarafa, Charaf; Remold‐O′Donnell, Eileen

doi:10.1093/infdis/jir352

Cited by 55 publications

(64 citation statements)

References 46 publications

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“…[12][13][14]49 In this context, we have previously shown that serpinB1 contributes to prevent increased mortality and morbidity associated with production of inflammatory cytokines upon infection with Pseudomonas aeruginosa and influenza A virus. 20,50 In this study, we demonstrate that serpinB1 inhibition of the primary granule protease CG in PMNs is essential for PMN survival and this ultimately regulates PMN numbers in vivo. Our findings also extend the roles of CG from antimicrobial and immunoregulatory functions to a novel role in inducing cell death.…”

Section: Discussionmentioning

confidence: 65%

SerpinB1 is critical for neutrophil survival through cell-autonomous inhibition of cathepsin G

Baumann

Pham

Benarafa

2013

Blood

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• Serine protease inhibitor serpinB1 protects neutrophils by inhibition of their own azurophil granule protease cathepsin G.• Granule permeabilization in neutrophils leads to cathepsin G-mediated death upstream and independent of apoptotic caspases.Bone marrow (BM) holds a large reserve of polymorphonuclear neutrophils (PMNs) that are rapidly mobilized to the circulation and tissues in response to danger signals. SerpinB1 is a potent inhibitor of neutrophil serine proteases neutrophil elastase (NE) and cathepsin G (CG). SerpinB1 deficiency (sB1) results in a severe reduction of the BM PMN reserve and failure to clear bacterial infection. Using BM chimera, we found that serpinB1 deficiency in BM cells was necessary and sufficient to reproduce the BM neutropenia of sB1 2/2 mice.Moreover, we showed that genetic deletion of CG, but not NE, fully rescued the BM neutropenia in sB1 2/2 mice. In mixed BM chimera and in vitro survival studies, we showed that CG modulates sB1 2/2 PMN survival through a cell-intrinsic pathway. In addition, membrane permeabilization by lysosomotropic agent L-leucyl-L-leucine methyl ester that allows cytosolic release of granule contents was sufficient to induce rapid PMN death through a CG-dependent pathway. CG-mediated PMN cytotoxicity was only partly blocked by caspase inhibition, suggesting that CG cleaves a distinct set of targets during apoptosis. In conclusion, we have unveiled a new cytotoxic function for the serine protease CG and showed that serpinB1 is critical for maintaining PMN survival by antagonizing intracellular CG activity. (Blood. 2013;121(19):3900-3907)

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Section: Discussionmentioning

confidence: 65%

SerpinB1 is critical for neutrophil survival through cell-autonomous inhibition of cathepsin G

Baumann

Pham

Benarafa

2013

Blood

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“…These results indicated that SERPINB1 promoted STAT3/HO-1 activation to confer its pulmonary protective effects in ALI was through ERK1/2. number than that of wild-type mice, which associated with elevated cytokines and chemokines concentrations in the lung 34 . Results from our current study provided additional evidences that SERPINB1 conferred pulmonary protection not only through its anti-inflammatory effects but also from its antioxidant property.…”

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confidence: 90%

SERPINB1 ameliorates acute lung injury in liver transplantation through ERK1/2-mediated STAT3-dependent HO-1 induction

Yao

Luo

et al. 2017

Free Radical Biology and Medicine

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“…Neutrophils are protected by serpinB1 from a cellintrinsic death pathway mediated by CG, which induces neutrophil death both upstream and independently of caspases (2,4). In highly acute neutrophil inflammation caused by bacterial and viral infections, we showed that reduced neutrophil survival led to an overwhelming inflammation, increased tissue injury, and, ultimately, increased mortality in serpinB1a KO mice (5,20). In the emphysema model, neutrophil recruitment is considerably lower than in infectious settings, and the rapid demise of neutrophils may ultimately be less damaging, and thus, not associated with increased lung damage in KO mice after cigarette smoke exposure.…”

Section: Discussionmentioning

confidence: 82%

“…Furthermore, rats or serpinB1a-deficient mice treated with recombinant SERPINB1 showed increased Pseudomonas clearance and reduced associated inflammation (5,55). In addition, serpinB1a-deficient mice showed increased lung injury, morbidity, and mortality following influenza A virus infection (20). These findings demonstrate that SERPINB1 is a critical regulator of neutrophil proteases during lung infection.…”

mentioning

confidence: 77%

SerpinB1 deficiency is not associated with increased susceptibility to pulmonary emphysema in mice

Cremona

Tschanz

Garnier

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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Cremona TP, Tschanz SA, von Garnier C, Benarafa C. SerpinB1 deficiency is not associated with increased susceptibility to pulmonary emphysema in mice. Am J Physiol Lung Cell Mol Physiol 305: L981-L989, 2013. First published October 25, 2013 doi:10.1152/ajplung.00181.2013.-Chronic obstructive pulmonary disease (COPD) is characterized by emphysema and chronic bronchitis and is a leading cause of morbidity and mortality worldwide. Tobacco smoke and deficiency in ␣1-antitrypsin (AAT) are the most prominent environmental and genetic risk factors, respectively. Yet the pathogenesis of COPD is not completely elucidated. Disease progression appears to include a vicious circle driven by self-perpetuating lung inflammation, endothelial and epithelial cell death, and proteolytic degradation of extracellular matrix proteins. Like AAT, serpinB1 is a potent inhibitor of serine proteases including neutrophil elastase and cathepsin G. Because serpinB1 is expressed in myeloid and lung epithelial cells and is protective during lung infections, we investigated the role of serpinB1 in preventing age-related and cigarette smoke-induced emphysema in mice. Fifteen-month-old mice showed increased lung volume and decreased pulmonary function compared with young adult mice (3 mo old), but no differences were observed between serpinB1-deficient (KO) and wild-type (WT) mice. Chronic exposure to secondhand cigarette smoke resulted in structural emphysematous changes compared with respective control mice, but no difference in lung morphometry was observed between genotypes. Of note, the different pattern of stereological changes induced by age and cigarette smoke suggest distinct mechanisms leading to increased airway volume. Finally, expression of intracellular and extracellular protease inhibitors were differently regulated in lungs of WT and KO mice following smoke exposure; however, activity of proteases was not significantly altered. In conclusion, we showed that, although AAT and serpinB1 are similarly potent inhibitors of neutrophil proteases, serpinB1 deficiency is not associated with more severe emphysema. serpin; cigarette smoke; animal model THIS YEAR MARKS the 50th anniversary of the landmark study by Laurell and Eriksson (33) that describes the association between reduced levels of the plasma protein ␣1-antitrypsin (AAT) and early development of severe pulmonary emphysema. The characterization of AAT as a major inhibitor of neutrophil elastase (NE) and the replication of features of emphysema following instillation of NE in the lungs of laboratory animals have been fundamental evidence in support of the protease-antiprotease theory of emphysema development (28,29,43,45,51,52). According to the theory, unopposed proteolytic activity of NE against elastin in the lungs leads to the degradation of this essential extracellular matrix protein, which normally provides the vital elastic properties of the lungs. Studies using animal models and knockout mice have helped extend and refine the protease-antiprotease theory beyond NE and AAT...

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Critical Role of SerpinB1 in Regulating Inflammatory Responses in Pulmonary Influenza Infection

Abstract: Because viral clearance was unimpaired, the study highlights the critical role of serpinB1 in mitigating inflammation and restricting pro-inflammatory cytokine production in influenza infection.

Cited by 55 publications

References 46 publications

SerpinB1 is critical for neutrophil survival through cell-autonomous inhibition of cathepsin G

SerpinB1 is critical for neutrophil survival through cell-autonomous inhibition of cathepsin G

SERPINB1 ameliorates acute lung injury in liver transplantation through ERK1/2-mediated STAT3-dependent HO-1 induction

SerpinB1 deficiency is not associated with increased susceptibility to pulmonary emphysema in mice

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