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Of Human Neutrophils Catch and Hold Salmonella Enterica Serovar Typhimurium at a Distance from the Cell Surface Svetlana I

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Of Human Neutrophils Catch and Hold Salmonella Enterica Serovar Typhimurium at a Distance from the Cell Surface Svetlana I RESEARCH ARTICLE Nitric oxide-induced membrane tubulovesicular extensions (cytonemes) of human neutrophils catch and hold Salmonella enterica serovar Typhimurium at a distance from the cell surface Svetlana I. Galkina1, Julia M. Romanova2, Vladimir I. Stadnichuk3, Julian G. Molotkovsky4, Galina F. Sud’ina1 & Thomas Klein5 1A. N. Belozersky Institute, Moscow State University, Moscow, Russia; 2The Gamaleya Research Institute of Epidemiology and Microbiology RAMS, Moscow, Russia; 3Physical Department of Moscow State University, Moscow, Russia; 4Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Downloaded from https://academic.oup.com/femspd/article/56/2/162/517509 by guest on 27 September 2021 Academy of Sciences, Moscow, Russia; and 5Boehringer Ingelheim Pharma, Biberach, Germany Correspondence: Svetlana I. Galkina, A. N. Abstract Belozersky Institute, Moscow State University, Leninskie gory, Building A, Moscow 119991, Nitric oxide (NO) plays an important role in host defense against bacterial Russia. Tel.: 17 495 939 54 08; fax: 17495 infections such as salmonellosis. NO and 4-bromophenacyl bromide (BPB) induce 939 31 81; e-mail: [email protected] the formation of long tubulovesicular extensions (TVE, cytonemes, membrane tethers) from human neutrophils. These TVE serve as cellular sensory and adhesive Received 10 October 2008; revised 11 March organelles. In the present study, we demonstrated that in the presence of the NO 2009; accepted 20 March 2009. donor, diethylamine NONOate or BPB human neutrophils bound and aggregated Final version published online 27 April 2009. Salmonella enterica serovar Typhimurium bacteria extracellularly by TVE. In o contrast, inhibition of NO-synthase activity by N -nitro-L-arginine methyl ester DOI:10.1111/j.1574-695X.2009.00560.x stimulated neutrophil phagocytosis (ingestion) of bacteria. Neutrophil TVE consisted of membrane-covered cytoplasm as was shown by the fluorescent Editor: Willem van Eden cytoplasmic dye 20,70-bis(2carboxyethyl)-5,(6)-carboxyfluorescein, and the fluor- Keywords escent lipid, BODIPY-labeled sulfatide. Disruption and shedding of TVE were nitric oxide; neutrophil; tubulovesicular accompanied by the appearance of specific invaginations (porosomes) on neu- extensions; membrane tethers; cytonemes; trophil cell bodies. These invaginations corresponded to the variations in diameter Salmonella enterica serovar Typhimurium. of TVE (160–240 nm). We hypothesized that TVE represented protrusions of neutrophil exocytotic trafficking through special structures on the neutrophil surface. In conclusion, we propose a novel mechanism by which NO-induced TVE formation enables neutrophils to bind and aggregate bacteria at a distance. Formation of long and thin cellular protrusions which Introduction connect cells to substrata and to other cells is a wide-spread Neutrophils play a key role in host-defense mechanisms phenomenon, that is observed in various embryonic cells against invading pathogens because of their capacity to (Galkina et al., 2006a), blood cells (Shao et al., 1998; penetrate inflamed tissue and kill microorganisms. They Schmidtke & Diamond, 2000; Galkina et al., 2001, 2005, phagocytose bacteria intracellularly, but the bacteria often 2006b; Raghunathan et al., 2001; Marcus & Hochmuth, survive and multiply inside the phagocytes. Neutrophils are 2002; Park et al., 2002; Gupta & DeFranco, 2003; Onfelt also able to secrete bactericide for extracellular killing of et al., 2004; Ramachandran et al., 2004; Watkins & Salter, pathogens. The disadvantage is that the bactericide is 2005), nerve cells (Rustom et al., 2004) and astrocytes strongly diluted in the extracellular medium and can destroy (Gimsa et al., 2007). Because of the resolution limitations host tissues along with the bacteria. Here, we report on a of optic microscopy, these structures have not been new type of neutrophil interaction with bacteria. Human studied extensively. They vary very much in size, origin and neutrophils demonstrate long-range extracellular catching behavior in different works. Neutrophil TVE are character- and holding of bacteria by nitric oxide (NO)-induced thin ized by the uniform diameter along the entire length and very long membrane tubulovesicular extensions (TVE, (varying from 80 to 400 nm depending on different condi- cytonemes, membrane tethers). tions), their outstanding length, high developmental rate c 2009 Federation of European Microbiological Societies FEMS Immunol Med Microbiol 56 (2009) 162–171 Published by Blackwell Publishing Ltd. All rights reserved Bacteria binding by neutrophil membrane extensions 163 (1–5 mm minÀ1), flexibility and motility (for extensions with reactive NO radicals and reactive oxygen species produced nonattached tips). by phagocytes may determine the ability of phagocytes to Flowing neutrophils are capable of developing ultralong kill bacteria. membrane tethers that attach to spread platelets or immo- We thus hypothesized that numerous NO-induced TVE bilized P-selectin under shear stress (Schmidtke & Diamond, would widen the area within which neutrophils could capture 2000; Park et al., 2002; Ramachandran et al., 2004). These bacteria. Salmonella enterica serovar Typhimurium is the tethers are known to stabilize neutrophil rolling velocities. primary agent of food poisoning in humans and the causative Thin membrane tethers can be pulled from the neutrophil agent of typhoid fever-like disease in mice and immunocom- bodies with a micropipette manipulation (Shao et al., 1998; promised humans. To test our hypothesis we compared Marcus & Hochmuth, 2002). Neutrophil adhesion to fibro- neutrophil interactions with S. Typhimurium in the presence 1 nectin-coated substrata in Na -free extracellular medium, or absence of an NO synthase inhibitor or an NO donor. To Downloaded from https://academic.oup.com/femspd/article/56/2/162/517509 by guest on 27 September 2021 or in the presence of chloride channel inhibitors, or actin- investigate the mechanism of TVE formation, especially the disrupting agents such as cytochalasin D and B or the size, length and diameter of the TVE, we also studied alkylating agent 4-bromophenacyl bromide (BPB) leads to neutrophil interaction with bacteria in the presence of BPB. membrane TVE formation and growth (Galkina et al., 2001). BPB can affect the actin cytoskeleton through Materials and methods a leukocyte-specific actin-bundling protein, L-plastin o (Rosales et al., 1994). BPB is also known to inhibit secretory Bicarbonate-free Hank’s solution, BPB, N -nitro-L-arginine forms of phospholipase A2, playing an essential role in methyl ester (L-NAME), cholesterol sulfate and bovine brain adhesion and degranulation of neutrophils and mast cells sulfatide (predominantly galactosylceramide sulfate) were (Jacobson & Schrier, 1993; Enomoto et al., 2000). It is one of purchased from Sigma (Steinheim, Germany). Ficoll-Paque the most reliable inducers of cytoneme formation in neu- was purchased from Pharmacia (Uppsala, Sweden). Fibro- trophils, capable of evoking TVE formation in >90% of nectin was from Calbiochem (La Jolla). Diethylamine NON- neutrophils (Galkina et al., 2001). Inhibition of glucose Oate (diethylamine dinitric oxide) and sulfo-NONOate were metabolism or blocking of ATPase (vacuolar type) also from Cayman (Massy, France). Acetoxymethyl ester of 20,70- initiates formation of TVE on the neutrophil cell bodies bis(2carboxyethyl)-5,(6)-carboxyfluorescein (BCECF) was (Galkina et al., 2001, 2006a, b). obtained from Molecular Probes (Eugene, OR). BODIPY- 0 We have previously shown that NO, a powerful physiolo- sufatide, 3-O-sulfo-D-galactosyl-b1-1 -N-[7-(4,4-difluoro-1, gical regulator of neutrophil adhesive interactions (Kubes 3,5,7-tetramethyl-4-bora-3a,4a-diaza-S-indacene-8-yl)hep- et al., 1991; Moncada et al., 1991), induces TVE formation, tanoyl]-D-erythro-sphingosine, was prepared by a standard which interconnects neutrophils and results in the binding procedure used for such compounds (Koshy & Boggs, 1983); of particles for phagocytosis, such as opsonized zymosan details of the synthesis will be published elsewhere. particles or erythrocytes (Galkina et al., 2005). Both exogen- For neutrophil preparation we used the blood of healthy ous NO produced by endothelium and other tissues (Sessa, volunteers with no pharmacological therapy in the 2 weeks 1994), as well as endogenous NO produced by neutrophils preceding sampling. Blood was taken via venous puncture as themselves, could affect neutrophil adhesive interaction. approved by Ministry of Public Health Service of Russian Constitutive neuronal type NO synthase (Wallerath et al., Federation. Blood experimental procedures were approved 1997) and inducible NO synthase (Greenberg et al., 1998) by the Institutional Ethics Committee of the A. N. Belozers- are known to be present in neutrophils. ky Institute. Neutrophils were isolated from freshly drawn NO plays an important role in host defense against blood on a bilayer gradient of Ficoll-Paque (at densities multiple bacterial infections, including salmonellosis (Ume- 1.077 and 1.125 g mLÀ1) (Boyum, 1974). Washed neutro- zawa et al., 1997; MacFarlane et al., 1999; Mastroeni et al., phils were resuspended in bicarbonate-free Hank’s solution 2000; Vazquez-Torres et al., 2000; Alam et al., 2002; Klink containing 10 mM HEPES, pH 7.35. Glass cover slips were et al., 2003; McCollister et al., 2005; Klink et al., 2007). To incubated in Hank’s solution containing 5 mgmLÀ1 fibro- resist the antimicrobial action of NO produced by host
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