Azithromycin Augments Bacterial Uptake and Anti-Inflammatory Macrophage Polarization in Cystic Fibrosis

被引:4
作者
Tarique, Abdullah A. [1 ]
Tuladhar, Neeraj [2 ]
Kelk, Dean [1 ]
Begum, Nelufa [1 ]
Lucas, Richard M. [2 ]
Luo, Lin [2 ]
Stow, Jennifer L. [2 ]
Wainwright, Claire E. [1 ,3 ]
Bell, Scott C. [1 ,4 ]
Sly, Peter D. [1 ]
Fantino, Emmanuelle [1 ]
机构
[1] Univ Queensland, Child Hlth Res Ctr CHRC, Brisbane, Qld 4101, Australia
[2] Univ Queensland, Inst Mol Biosci IMB, Brisbane, Qld 4067, Australia
[3] Queensland Childrens Hosp, Resp & Sleep Med, Brisbane, Qld 4101, Australia
[4] Prince Charles Hosp, Thorac Med, Brisbane, Qld 4032, Australia
关键词
cystic fibrosis; CFTR; phagocytosis; bacterial killing; Pseudomonas aeruginosa; macrophage polarization; ERK1/2; azithromycin; antibiotic resistance; PHAGOCYTOSIS; ACTIVATION; MACROLIDES; CHILDREN;
D O I
10.3390/cells13020166
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Background: Azithromycin (AZM) is widely being used for treating patients with cystic fibrosis (pwCF) following clinical trials demonstrating improved lung function and fewer incidents of pulmonary exacerba-tions. While the precise mechanisms remain elusive, immunomodulatory actions are thought to be involved. We previously reported impaired phagocytosis and defective anti-inflammatory M2 macrophage polarization in CF. This study systematically analyzed the effect of AZM on the functions of unpolarized and M1/M2 polarized macrophages in CF. Methods: Monocytes, isolated from the venous blood of patients with CF (pwCF) and healthy controls (HCs), were differentiated into monocyte-derived macrophages (MDMs) and subsequently infected with P. aeruginosa. P. aeruginosa uptake and killing by MDMs in the presence or absence of AZM was studied. M1 and M2 macrophage polarizations were induced and their functions and cytokine release were analyzed. Results: Following AZM treatment, both HC and CF MDMs exhibited a significant increase in P. aeruginosa uptake and killing, however, lysosomal acidification remained unchanged. AZM treatment led to higher activation of ERK1/2 in both HC and CF MDMs. Pharmacological inhibition of ERK1/2 using U0126 significantly reduced P. aeruginosa uptake in HC MDMs. M1 macrophage polarization remained unaffected; however, AZM treatment led to increased IL-6 and IL-10 release in both HC and CF M1 macrophages. AZM also significantly increased the phagocytic index for both pHrodo E. coli and S. aureus in CF M1 macrophages. In CF, AZM treatment promoted anti-inflammatory M2 macrophage polarization, with an increased percentage of CD209+ M2 macrophages, induction of the M2 gene CCL18, along with its secretion in the culture supernatant. However, AZM d'd not restore endocytosis in CF, another essential feature of M2 macrophages. Conclusions: This study highlights the cellular functions and molecular targets of AZM which may involve an improved uptake of both Gram-positive and Gram-negative bacteria, restored anti-inflammatory macrophage polarization in CF. This may in turn shape the reduced lung inflammation observed in clinical trials. In addition, we confirmed the role of ERK1/2 activation for bacterial uptake.
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页数:13
相关论文
共 30 条
[1]   Uncoupling of IL-6 signaling and LC3-associated phagocytosis drives immunoparalysis during sepsis [J].
Akoumianaki, Tonia ;
Vaporidi, Katerina ;
Diamantaki, Eleni ;
Pene, Frederic ;
Beau, Remi ;
Gresnigt, Mark S. ;
Gkountzinopulou, Marina ;
Venichaki, Maria ;
Drakos, Elias ;
El-Benna, Jamel ;
Samonis, George ;
Le, Kieu T. T. ;
Kumar, Vinod ;
Georgopoulos, Dimitrios ;
van de Veerdonk, Frank L. ;
Netea, Mihai G. ;
Latge, Jean-Paul ;
Chamilos, Georgios .
CELL HOST & MICROBE, 2021, 29 (08) :1277-+
[2]  
BALDWIN DR, 1990, EUR RESPIR J, V3, P886
[3]   Localized Diacylglycerol-dependent Stimulation of Ras and Rap1 during Phagocytosis [J].
Botelho, Roberto J. ;
Harrison, Rene E. ;
Stone, James C. ;
Hancock, John F. ;
Philips, Mark R. ;
Jongstra-Bilen, Jenny ;
Mason, David ;
Plumb, Jonathan ;
Gold, Michael R. ;
Grinstein, Sergio .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284 (42) :28522-28532
[4]   MEK1 dependent and independent ERK activation regulates IL-10 and IL-12 production in bone marrow derived macrophages [J].
Bouhamdan, Mohamad ;
Bauerfeld, Christian ;
Talreja, Jaya ;
Beuret, Laurent ;
Charron, Jean ;
Samavati, Lobelia .
CELLULAR SIGNALLING, 2015, 27 (10) :2068-2076
[5]   Long term effects of azithromycin in patients with cystic fibrosis: a double blind, placebo controlled trial [J].
Clement, A. ;
Tamalet, A. ;
Leroux, E. ;
Ravilly, S. ;
Fauroux, B. ;
Jais, J-P .
THORAX, 2006, 61 (10) :895-902
[6]   CFTR regulates phagosome acidification in macrophages and alters bactericidal activity [J].
Di, Anke ;
Brown, Mary E. ;
Deriy, Ludmila V. ;
Li, Chunying ;
Szeto, Frances L. ;
Chen, Yimei ;
Huang, Ping ;
Tong, Jiankun ;
Naren, Anjaparavanda P. ;
Bindokas, Vytautas ;
Palfrey, H. Clive ;
Nelson, Deborah J. .
NATURE CELL BIOLOGY, 2006, 8 (09) :933-U52
[7]   Long term azithromycin in children with cystic fibrosis: a randomised, placebo-controlled crossover trial [J].
Equi, A ;
Balfour-Lynn, IM ;
Bush, A ;
Rosenthal, M .
LANCET, 2002, 360 (9338) :978-984
[8]   The TAK1→IKKβ→TPL2→MKK1/MKK2 Signaling Cascade Regulates IL-33 Expression in Cystic Fibrosis Airway Epithelial Cells Following Infection by Pseudomonas aeruginosa [J].
Farias, Raquel ;
Rousseau, Simon .
FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY, 2016, 3
[9]   Inflammatory Macrophage Expansion in Pulmonary Hypertension Depends upon Mobilization of Blood-Borne Monocytes [J].
Florentin, Jonathan ;
Coppin, Emilie ;
Vasamsetti, Sathish Babu ;
Zhao, Jingsi ;
Tai, Yi-Yin ;
Tang, Ying ;
Zhang, Yingze ;
Watson, Annie ;
Sembrat, John ;
Rojas, Mauricio ;
Vargas, Sara O. ;
Chan, Stephen Y. ;
Dutta, Partha .
JOURNAL OF IMMUNOLOGY, 2018, 200 (10) :3612-3625
[10]   Azithromycin Polarizes Macrophages to an M2 Phenotype via Inhibition of the STAT1 and NF-κB Signaling Pathways [J].
Haydar, Dalia ;
Cory, Theodore J. ;
Birket, Susan E. ;
Murphy, Brian S. ;
Pennypacker, Keith R. ;
Sinai, Anthony P. ;
Feola, David J. .
JOURNAL OF IMMUNOLOGY, 2019, 203 (04) :1021-1030