Recruitment of monocytes primed to express heme oxygenase-1 ameliorates pathological lung inflammation in cystic fibrosis
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Overwhelming neutrophilic inflammation is a leading cause of lung damage in many pulmonary diseases, including cystic fibrosis (CF). The heme oxygenase-1 (HO-1)/carbon monoxide (CO) pathway mediates the resolution of inflammation and is defective in CF-affected macrophages (MΦs). Here, we provide evidence that systemic administration of PP-007, a CO releasing/O2 transfer agent, induces the expression of HO-1 in a myeloid differentiation factor 88 (MyD88) and phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT)-dependent manner. It also rescues the reduced HO-1 levels in CF-affected cells induced in response to lipopolysaccharides (LPS) or Pseudomonas aeruginosa (PA). Treatment of CF and muco-obstructive lung disease mouse models with a single clinically relevant dose of PP-007 leads to effective resolution of lung neutrophilia and to decreased levels of proinflammatory cytokines in response to LPS. Using HO-1 conditional knockout mice, we show that the beneficial effect of PP-007 is due to the priming of circulating monocytes trafficking to the lungs in response to infection to express high levels of HO-1. Finally, we show that PP-007 does not compromise the clearance of PA in the setting of chronic airway infection. Overall, we reveal the mechanism of action of PP-007 responsible for the immunomodulatory function observed in clinical trials for a wide range of diseases and demonstrate the potential use of PP-007 in controlling neutrophilic pulmonary inflammation by promoting the expression of HO-1 in monocytes/macrophages.
Abstract
Overwhelming neutrophilic inflammation is a leading cause of lung damage in many pulmonary diseases, including cystic fibrosis (CF). The heme oxygenase-1 (HO-1)/carbon monoxide (CO) pathway mediates the resolution of inflammation and is defective in CF-affected macrophages (MΦs). Here, we provide evidence that systemic administration of PP-007, a CO releasing/O2 transfer agent, induces the expression of HO-1 in a myeloid differentiation factor 88 (MyD88) and phosphatidylinositol 3-kinase (PI3K)/ protein kinase B (AKT)-dependent manner. It also rescues the reduced HO-1 levels in CF-affected cells induced in response to lipopolysaccharides (LPS) or Pseudomonas aeruginosa (PA). Treatment of CF and muco-obstructive lung disease mouse models with a single clinically relevant dose of PP-007 leads to effective resolution of lung neutrophilia and to decreased levels of proinflammatory cytokines in response to LPS. Using HO-1 conditional knockout mice, we show that the beneficial effect of PP-007 is due to the priming of circulating monocytes trafficking to the lungs in response to infection to express high levels of HO-1. Finally, we show that PP-007 does not compromise the clearance of PA in the setting of chronic airway infection. Overall, we reveal the mechanism of action of PP-007 responsible for the immunomodulatory function observed in clinical trials for a wide range of diseases and demonstrate the potential use of PP-007 in controlling neutrophilic pulmonary inflammation by promoting the expression of HO-1 in monocytes/macrophages.
참고문헌 (49)
- Cantin, A. M., "Inflammation in cystic fibrosis lung disease : pathogenesis and therapy", J. Cyst. Fibros, 14, pp.419~430 (2015)
- Mogayzel, P. J. Jr., "Cystic fibrosis pulmonary guidelines. Chronic medications for maintenance of lung health", Am. J. Respir. Crit. Care Med, 187, pp.680~689 (2013)
- Konstan, M. W., "A randomized double blind, placebo controlled phase 2 trial of BIIL 284 BS (an LTB4 receptor antagonist) for the treatment of lung disease in children and adults with cystic fibrosis", J. Cyst. Fibros, 13, pp.148~155 (2014)
- Middleton, P. G., "Elexacaftor-tezacaftor-ivacaftor for cystic fibrosis with a single Phe508del allele", N. Engl. J. Med, 381, pp.1809~1819 (2019)
- Heijerman, H. G. M., "Efficacy and safety of the elexacaftor plus tezacaftor plus ivacaftor combination regimen in people with cystic fibrosis homozygous for the F508del mutation: a double-blind, randomised, phase 3 trial", Lancet, 394, pp.1940~1948 (2019)
- Harris, J. K., "Changes in airway microbiome and inflammation with ivacaftor treatment in patients with cystic fibrosis and the G551D mutation", Ann. Am. Thorac. Soc, 17, pp.212~220 (2020)
- Bruscia, E. B., "Innate and adaptive immunity in cystic fibrosis", Clin. Chest Med, 37, pp.17~29 (2016)
- Bruscia, E. M., "Cystic fibrosis lung immunity : the role of the macrophage", J. Innate Immun, 8, pp.550~563 (2016)
- Zhang, P. X., "Reduced caveolin-1 promotes hyperinflammation due to abnormal heme oxygenase-1 localization in lipopolysaccharide-challenged macrophages with dysfunctional cystic fibrosis transmembrane conductance regulator", J. Immunol, 190, pp.5196~5206 (2013)
- Zhang, P. X., "Pharmacological modulation of the AKT", microRNA-199a-5p, Nat. Commun, pp.2015, 6[DOI]
- Di Pietro, C., "Ezrin links CFTR to TLR4 signaling to orchestrate anti-bacterial immune response in macrophages", Sci. Rep, 7, pp.10882~ (2017)
- Choi, A. M., "Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidant-induced lung injury", Am. J. Respir. Cell. Mol. Biol, 15, pp.9~19 (1996)
- Bilban, M., "Heme oxygenase and carbon monoxide initiate homeostatic signaling", J. Mol. Med, 86, pp.267~279 (2008)
- Soares, M. P., "Immunoregulatory effects of HO-1 : how does it work? Curr", Opin. Pharmacol, 9, pp.482~489 (2009)
- Di Pietro, C., "Targeting the heme oxygenase 1", carbon monoxide pathway to resolve lung hyper-inflammation and restore a regulated immune response in cystic fibrosis, 2020, pp.11, 1059~
- Dalli, J., "The regulation of proresolving lipid mediator profiles in baboon pneumonia by inhaled carbon monoxide", Am. J. Respir. Cell. Mol. Biol, 53, pp.314~325 (2015)
- Motterlini, R., "The therapeutic potential of carbon monoxide", Nat. Rev. Drug Discov, 9, pp.728~743 (2010)
- Otterbein, L. E., "Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway", Nat. Med, 6, pp.422~428 (2000)
- Ryter, S. W., "Carbon monoxide in lung cell physiology and disease", Am. J. Physiol. Cell. Physiol, 314, pp.C211~C227 (2018)
- Ji, X., "Toward carbon monoxide-based therapeutics : critical drug delivery and developability issues", J. Pharm. Sci, 105, pp.406~416 (2016)
- Rosas, I. O., "A phase II clinical trial of low-dose inhaled carbon monoxide in idiopathic pulmonary fibrosis", Chest, 153, pp.94~104 (2018)
- Fredenburgh, L. E., "A phase I trial of low-dose inhaled carbon monoxide in sepsis-induced ARDS", JCI Insight, 3, pp.e124039~ (2018)
- Bathoorn, E., "Anti-inflammatory effects of inhaled carbon monoxide in patients with COPD: a pilot study", Eur. Respir. J, 30, pp.1131~1137 (2007)
- Abuchowski, A., "PEGylated bovine carboxyhemoglobin (SANGUINATE): results of clinical safety testing and use in patients", Adv. Exp. Med. Biol, 876, pp.461~467 (2016)
- Abuchowski, A., "SANGUINATE (PEGylated carboxyhemoglobin bovine): mechanism of action and clinical update", Artif. Organs, 41, pp.346~350 (2017)
- Bassam G. Abu Jawdeh, "A phase Ib, open-label, single arm study to assess the safety, pharmacokinetics, and impact on humoral sensitization of SANGUINATE infusion in patients with end-stage renal disease", Clinical Transplantation, 32(1), pp.e13155~ (2017), Wiley[DOI]
- Misra, H., "PEGylated carboxyhemoglobin bovine(SANGUINATE) : results of a phase I clinical trial", Artif. Organs, 38, pp.702~707 (2014)
- Misra, H., "A Phase Ib open label, randomized, safety study of SANGUINATE in patients with sickle cell anemia", Rev. Bras. Hematol. Hemoter, 39, pp.20~27 (2017)
- Dhar, R., "SANGUINATE(PEGylated carboxyhemoglobin bovine)improves cerebral blood flow to vulnerable brain regions at risk of delayed cerebral ischemia after subarachnoid hemorrhage", Neurocrit. Care, 27, pp.341~349 (2017)
- Sam, C., "Pegylated bovine carboxyhaemoglobin utilisation in a thrombotic thrombocytopenic purpura patient", Transfus. Med, 27, pp.300~302 (2017)
- Bruscia, E. M., "Macrophages directly contribute to the exaggerated inflammatory response in cystic fibrosis transmembrane conductance regulator-", - mice, 2009, pp.40, 295~304
- Bruscia, E. M., "Abnormal trafficking and degradation of TLR4 underlie the elevated inflammatory response in cystic fibrosis", J. Immunol, 186, pp.6990~6998 (2011)
- Cho, H., "Akt1", PKBalpha is required for normal growth but dispensable for maintenance of glucose homeostasis in mice, 2001, pp.276, 38349~38352
- Mall, M., "Increased airway epithelial Na+ absorption produces cystic fibrosis-like lung disease in mice", Nat. Med, 10, pp.487~493 (2004)
- Mamiya, T., "Hepatocyte-specific deletion of heme oxygenase-1 disrupts redox homeostasis in basal and oxidative environments", Tohoku J. Exp. Med, 216, pp.331~339 (2008)
- Wegiel, B., "Macrophages sense and kill bacteria through carbon monoxidedependent inflammasome activation", J. Clin. Invest, 124, pp.4926~4940 (2014)
- Yona, S., "Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis", Immunity, 38, pp.79~91 (2013)
- van Heeckeren, A., "Excessive inflammatory response of cystic fibrosis mice to bronchopulmonary infection with Pseudomonas aeruginosa", J. Clin. Invest, 100, pp.2810~2815 (1997)
- Rosenjack, J., "HDAC6 depletion improves cystic fibrosis mouse airway responses to bacterial challenge", Sci. Rep, 9, pp.10282~ (2019)
- Laird, M. H., "TLR4", MyD88, J. Leukoc. Biol, pp.2009, 85[DOI]
- Torphy, T. J., "Considerations for the conduct of clinical trials with antiinflammatory agents in cystic fibrosis. A cystic fibrosis foundation workshop report", Ann. Am. Thorac. Soc, 12, pp.1398~1406 (2015)
- Zhang, M., "Myeloid HO-1 modulates macrophage polarization and protects against ischemia-reperfusion injury", JCI Insight, 3, pp.e120596~ (2018)
- Byrne, A. J., "Pulmonary macrophages : key players in the innate defence of the airways", Thorax, 70, pp.1189~1196 (2015)
- Yamasaki, K., "Lung macrophage phenotypes and functional responses: role in the pathogenesis of COPD", Int. J. Mol. Sci, 19, pp.582~ (2018)
- Rahman, K., "Inflammatory Ly6Chi monocytes and their conversion to M2macrophages drive atherosclerosis regression", J. Clin. Invest, 127, pp.2904~2915 (2017)
- Liegeois, M., "The interstitial macrophage: a long-neglected piece in the puzzle of lung immunity", Cell. Immunol, 330, pp.91~96 (2018)
- Maus, U. A., "Monocytes are potent facilitators of alveolar neutrophil emigration during lung inflammation : role of the CCL2-CCR2 axis", J. Immunol, 170, pp.3273~3278 (2003)
- Abu-El-Haija, M., "Pancreatic damage in fetal and newborn cystic fibrosis pigs involves the activation of inflammatory and remodeling pathways", Am. J. Pathol, 181, pp.499~507 (2012)
- Munck, A., "Cystic fibrosis : evidence for gut inflammation", Int. J. Biochem. Cell Biol, 52, pp.180~183 (2014)