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Azithromycin and Chloramphenicol Diminish Neutrophil Extracellular Traps (Nets) Release

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Azithromycin and Chloramphenicol Diminish Neutrophil Extracellular Traps (Nets) Release International Journal of Molecular Sciences Article Azithromycin and Chloramphenicol Diminish Neutrophil Extracellular Traps (NETs) Release Weronika Bystrzycka 1,2,3, Aneta Manda-Handzlik 1,3,*, Sandra Sieczkowska 2, Aneta Moskalik 2, Urszula Demkow 1 and Olga Ciepiela 1,* ID 1 Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Medical University of Warsaw, 02-091 Warsaw, Poland ; [email protected] (W.B.); [email protected] (U.D.) 2 Student’s Scientific Group at Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Medical University of Warsaw, 02-091 Warsaw, Poland; [email protected] (S.S.); [email protected] (A.M.) 3 Postgraduate School of Molecular Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland * Correspondence: [email protected] (A.M.-H.); [email protected] (O.C.); Tel.: +48-2231-79503 (A.M.-H.); +48-2231-79503 (O.C.) Received: 27 October 2017; Accepted: 5 December 2017; Published: 8 December 2017 Abstract: Neutrophils are one of the first cells to arrive at the site of infection, where they apply several strategies to kill pathogens: degranulation, respiratory burst, phagocytosis, and release of neutrophil extracellular traps (NETs). Antibiotics have an immunomodulating effect, and they can influence the properties of numerous immune cells, including neutrophils. The aim of this study was to investigate the effects of azithromycin and chloramphenicol on degranulation, apoptosis, respiratory burst, and the release of NETs by neutrophils. Neutrophils were isolated from healthy donors by density-gradient centrifugation method and incubated for 1 h with the studied antibiotics at different concentrations (0.5, 10 and 50 µg/mL—azithromycin and 10 and 50 µg/mL—chloramphenicol). Next, NET release was induced by a 3 h incubation with 100 nM phorbol 12-myristate 13-acetate (PMA). Amount of extracellular DNA was quantified by fluorometry, and NETs were visualized by immunofluorescent microscopy. Degranulation, apoptosis and respiratory burst were assessed by flow cytometry. We found that pretreatment of neutrophils with azithromycin and chloramphenicol decreases the release of NETs. Moreover, azithromycin showed a concentration-dependent effect on respiratory burst in neutrophils. Chloramphenicol did not affect degranulation, apoptosis nor respiratory burst. It can be concluded that antibiotics modulate the ability of neutrophils to release NETs influencing human innate immunity. Keywords: azithromycin; chloramphenicol; neutrophil extracellular traps 1. Introduction Neutrophils are the most abundant immune cells in human peripheral blood, and play a crucial role in the innate immune response by defending the body against pathogens. They are major antimicrobial effector cells designed to kill microbes by several strategies: degranulation, phagocytosis, generation of reactive oxygen species (ROS), and by the—recently discovered—release of neutrophil extracellular traps (NETs) in a process called NETosis. NETs are fragile fibers of decondensed chromatin decorated with antimicrobial proteins and histones [1]. These web-like structures are released from the cell to form a physical barrier for the pathogens that limits their spread throughout the organism, and to generate a high local concentration of antimicrobial factors. Despite their beneficial role, NETs have been also reported to contribute to the development of several diseases, including rheumatoid arthritis, diabetes, and thrombosis [2]. Therefore, a substantial effort is being made to identify agents modulating Int. J. Mol. Sci. 2017, 18, 2666; doi:10.3390/ijms18122666 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2017, 18, 2666 2 of 9 antimicrobial factors. Despite their beneficial role, NETs have been also reported to contribute to the development of several diseases, including rheumatoid arthritis, diabetes, and thrombosis [2]. Therefore, a substantial effort is being made to identify agents modulating the function of Int. J. Mol. Sci. 2017, 18, 2666 2 of 9 neutrophils, as this may help develop new therapeutic strategies for the treatment of patients suffering from NET-related diseases. the functionIt is proposed of neutrophils, that antibiotics as this may may help act develop as agents new therapeuticaffecting NET strategies release. for The the treatmentinfluence ofof patientsantibiotics suffering on the fromimmune NET-related system has diseases. been an object of investigation for nearly 70 years [3]. There are manyIt is proposed reports thatregarding antibiotics their may immunomodulati act as agents affectingng effect NET on release. granulocytic The influence and oflymphocytic antibiotics onfunctions the immune [4–6]. Hoeben system haset al. been have an demonstrated object of investigation that antibiotics for nearly affect 70the years respiratory [3]. There burst are activity many reportsand phagocytosis regarding their of immunomodulatingneutrophils [7]. Moreover, effect on Lai granulocytic et al. report and lymphocytic that azithromycin-loaded functions [4–6]. Hoebenneutrophils et al. are have more demonstrated effective in that bacterial antibiotics killing affect by thephagocytosis respiratory burst[8]. One activity of the and first phagocytosis groups to ofdescribe neutrophils the impact [7]. Moreover, of antibiot Lai etics al. on report the thatrelease azithromycin-loaded of NETs was Jerjomiceva neutrophils et are al. more, who effective observed in bacterialenhanced killing NETosis by phagocytosisin bovine granulocytes [8]. One of pretreated the first groups with toenrofloxacin describe the [9]. impact To date, of antibiotics there have on been the releasefew studies of NETs regarding was Jerjomiceva the impact et al.,of antibiotics who observed on NET enhanced release; NETosis thus, inwe bovine decided granulocytes to widen pretreatedknowledge withabout enrofloxacin this topic. There [9]. To are date, findings there concerning have been the few link studies between regarding antibiotic the impacttreatment of antibioticsand NETosis; on NEThowever, release; these thus, predominantly we decided to describe widen knowledge the induction about of thisNET topic. release There by the are addition findings concerningof bacteria theto the link cell between containing antibiotic the treatment antibiotic and [10,11]. NETosis; The however,aim of this these study predominantly was to investigate describe thechanges induction in the of functions NET release of neutrophils by the addition (NETosis, of bacteria degranulation, to the cell containingoxidative burst) the antibiotic caused [by10 ,11the]. Thepresence aim of of this antibiotics study was in tothe investigate cell medium. changes in the functions of neutrophils (NETosis, degranulation, oxidative burst) caused by the presence of antibiotics in the cell medium. 2. Results 2. Results 2.1. Degranulation 2.1. Degranulation Phorbol 12-myristate 13-acetate (PMA) was used as an inducer of degranulation during analysisPhorbol of the 12-myristate morphological 13-acetate complexity (PMA) of was neutro usedphils as an in inducer the side of degranulationscatter channel during (SSC) analysisby flow ofcytometry. the morphological We found complexitythat none of of the neutrophils studied antibiotics in the side alone scatter caused channel cell degranulation (SSC) by flow cytometry.(Figure 1). WeInstead, found we that found none that ofthe azithromycin studied antibiotics at doses alone of 10 caused and 50 cell μg/mL degranulation prevented (Figure cell degranulation1). Instead, weupon found PMA that treatment. azithromycin at doses of 10 and 50 µg/mL prevented cell degranulation upon PMA treatment. Figure 1. Effect of azithromycin and chloramphenicol on neutrophil degranulation assessed by Figure 1. Effect of azithromycin and chloramphenicol on neutrophil degranulation assessed by measuring the granularity degree of neutrophils in the side scatter channel (SSC). 100 nM phorbol measuring the granularity degree of neutrophils in the side scatter channel (SSC). 100 nM phorbol 12-myristate 13-acetate (PMA) was used as a positive control of degranulation (n ≥ 3) (* p ≤ 0.05 vs. 12-myristate 13-acetate (PMA) was used as a positive control of degranulation (n ≥ 3) (* p ≤ 0.05 vs. unstimulated (Un) cells). unstimulated (Un) cells). 2.2. Apoptosis 2.2. Apoptosis Incubation of granulocytes with antibiotics did not induce cells apoptosis, although a slight, non-significantIncubation increaseof granulocytes in the numberwith antibiotics of annexin did Vnot positive induce neutrophilscells apoptosis, compared although to a control, slight, untreatednon-significant cells wasincrease observed in the after number the incubation of annexi ofn the V cellspositive with 50neutrophilsµg/mL azithromycin compared to (Figure control,2). untreated cells was observed after the incubation of the cells with 50 μg/mL azithromycin (Figure 2). Int. J. Mol. Sci. Int. J. Mol. Sci. 20172017,, 1818,, 2666 2666 3 of 9 Int. J. Mol. Sci. 2017, 18, 2666 3 of 9 Figure 2. Effect of azithromycin and chloramphenicol on apoptosis assessed by annexin V-FITC and Figure 2. Effect of azithromycin and chloramphenicol on apoptosis assessed by annexin V-FITC and propodiumFigure 2. Effect iodide of azithromycinbinding; paraformaldehyde and chloramphenicol (PFA) constitutedon apoptosis positive assessed control by annexin (n = 6) V-FITC (** p ≤ 0.01and propodium iodide binding; paraformaldehyde (PFA) constituted positive control (n = 6) (** p ≤ 0.01
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