title: Protein-tyrosine phosphatase Shp2 positively regulates macrophage oxidative burst.
abstract: Macrophages are vital to innate immunity and express pattern recognition receptors and integrins for the rapid detection of invading pathogens. Stimulation of Dectin-1 and complement receptor 3 (CR3) activates Erk- and Akt-dependent production of reactive oxygen species (ROS). Shp2, a protein-tyrosine phosphatase encoded by Ptpn11, promotes activation of Ras-Erk and PI3K-Akt and is crucial for hematopoietic cell function; however, no studies have examined Shp2 function in particulate-stimulated ROS production. Maximal Dectin-1-stimulated ROS production corresponded kinetically to maximal Shp2 and Erk phosphorylation. Bone marrow-derived macrophages (BMMs) from mice with a conditionally deleted allele of Ptpn11 (Shp2(flox/flox);Mx1Cre+) produced significantly lower ROS levels compared with control BMMs. Although YFP-tagged phosphatase dead Shp2-C463A was strongly recruited to the early phagosome, its expression inhibited Dectin-1- and CR3-stimulated phospho-Erk and ROS levels, placing Shp2 phosphatase function and Erk activation upstream of ROS production. Further, BMMs expressing gain of function Shp2-D61Y or Shp2-E76K and peritoneal exudate macrophages from Shp2D61Y/+;Mx1Cre+ mice produced significantly elevated levels of Dectin-1- and CR3-stimulated ROS, which was reduced by pharmacologic inhibition of Erk. SIRPα (signal regulatory protein α) is a myeloid inhibitory immunoreceptor that requires tyrosine phosphorylation to exert its inhibitory effect. YFP-Shp2C463A-expressing cells have elevated phospho-SIRPα levels and an increased Shp2-SIRPα interaction compared with YFP-WT Shp2-expressing cells. Collectively, these findings indicate that Shp2 phosphatase function positively regulates Dectin-1- and CR3-stimulated ROS production in macrophages by dephosphorylating and thus mitigating the inhibitory function of SIRPα and by promoting Erk activation.
authors.affiliation: From the Department of Pediatrics, the Herman B Wells Center for Pediatric Research, and xl9@iu.edu.
authors.forename: Xing Jun
authors.initials: XJ
authors.lastname: Li
authors.affiliation: the Herman B Wells Center for Pediatric Research, and the Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Charles B
authors.initials: CB
authors.lastname: Goodwin
authors.affiliation: the Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Nabinger
authors.affiliation: the Herman B Wells Center for Pediatric Research, and the Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Briana M
authors.initials: BM
authors.lastname: Richine
authors.affiliation: West Coast University, Los Angeles, California 91606.
authors.forename: Zhenyun
authors.initials: Z
authors.lastname: Yang
authors.affiliation: From the Department of Pediatrics, the Herman B Wells Center for Pediatric Research, and the Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, the Department of Otorhinolaryngology and Head/Neck Surgery, Heinrich Heine University, 40225 Düsseldorf, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Hanenberg
authors.affiliation: the Gunma University Graduate School of Health Sciences, Maebashi, Gunma 371-8514, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ohnishi
authors.affiliation: the Kobe University Graduate School of Medicine, Chuo-Ku, Kobe 650-0017, Japan, and.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matozaki
authors.affiliation: the Department of Pathology, University of California, San Diego, La Jolla, California 92093.
authors.forename: Gen-Sheng
authors.initials: GS
authors.lastname: Feng
authors.affiliation: From the Department of Pediatrics, the Herman B Wells Center for Pediatric Research, and the Department of Medical & Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202, rchan@iu.edu.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Chan
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D047468:Immunoprecipitation; D019426:Integrases / Q000378:metabolism; D037181:Lectins, C-Type / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010587:Phagocytosis; D010766:Phosphorylation; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000502:physiology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D016897:Respiratory Burst / Q000502:physiology*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D000099181:Dectin-1
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D019426:Integrases; D037181:Lectins, C-Type; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D051057:Proto-Oncogene Proteins c-akt; D017382:Reactive Oxygen Species; D014443:Tyrosine; D000099181:Dectin-1; C045073:Cre recombinase; C516725:Ptpn11 protein, mouse
keywords: Macrophage; NADPH Oxidase; Pattern Recognition Receptor (PRR); Phagocytosis; Tyrosine-Protein Phosphatase (Tyrosine Phosphatase)