title: Distinct signalling mechanisms mediate neutrophil attraction to bacterial infection and tissue injury.
abstract: The signals that guide neutrophils to sites of tissue injury or infection remain elusive. H(2)O(2) has been implicated in neutrophil sensing of tissue injury and transformed cells; however, its role in neutrophil recruitment to infection has not been explored. Here, using a pharmacological inhibitor of NADPH oxidases, diphenyleneiodonium (DPI), and genetic depletion of an epithelial-specific NADPH oxidase, we show that H(2)O(2) is not required for neutrophil detection of localized infection with the Gram-negative bacterium Pseudomonas aeruginosa. In contrast, PI3K signalling is required for neutrophil responses to both wounding and infection. In vivo imaging using a H(2)O(2) probe detects dynamic H(2)O(2) generation at wounds but not at infected tissue. Moreover, DPI no longer inhibits neutrophil wound attraction when P. aeruginosa is present in the media. Finally, DPI also fails to inhibit neutrophil recruitment to localized infection with the Gram-positive bacterium, Streptococcus iniae. Our findings demonstrate that different signals are involved in sensitizing neutrophils to pathogen versus non-pathogen induced tissue damage, providing a potential target to preferentially suppress non-specific immune damage without affecting the response to infection.
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, WI 53706, USA. qdeng5@wisc.edu
authors.forename: Qing
authors.initials: Q
authors.lastname: Deng
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Harvie
authors.forename: Anna
authors.initials: A
authors.lastname: Huttenlocher
mesh_terms: D058500:Animal Fins / Q000187:drug effects / Q000276:immunology / Q000293:injuries*; D000818:Animals; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D004625:Embryo, Nonmammalian / Q000276:immunology / Q000382:microbiology; D004789:Enzyme Activation; D006861:Hydrogen Peroxide / Q000378:metabolism; D008845:Microinjections; D009025:Morpholines / Q000494:pharmacology; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000276:immunology / Q000378:metabolism / Q000382:microbiology*; D009861:Onium Compounds / Q000494:pharmacology; D010031:Otitis / Q000276:immunology / Q000382:microbiology; D010587:Phagocytosis; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011552:Pseudomonas Infections / Q000276:immunology* / Q000382:microbiology; D011550:Pseudomonas aeruginosa / Q000276:immunology / Q000472:pathogenicity; D015398:Signal Transduction; D013290:Streptococcal Infections / Q000276:immunology / Q000382:microbiology; D013291:Streptococcus / Q000276:immunology / Q000472:pathogenicity; D015027:Zebrafish / Q000196:embryology / Q000276:immunology / Q000382:microbiology*
chemical_list: D002867:Chromones; D009025:Morpholines; D009861:Onium Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C007517:diphenyleneiodonium; D006861:Hydrogen Peroxide; D019255:NADPH Oxidases; D058539:Phosphatidylinositol 3-Kinase