title: Receptor-interacting protein 2 controls pulmonary host defense to Escherichia coli infection via the regulation of interleukin-17A.
abstract: Recognition of microbial patterns by host receptors is the first step in a multistep sequence leading to neutrophil-dependent host resistance. Although the role of membrane-bound sensors in bacterial recognition has been examined in detail, the importance of cytosolic sensors in the lungs is largely unexplored. In this context, there is a major lack of understanding related to the downstream signaling mediators, such as cells and/or molecules, during acute extracellular Gram-negative bacterial pneumonia. In order to determine the role of NOD-like receptors (NLRs), we used an experimental Escherichia coli infection model using mice deficient in the gene coding for the NLR adaptor, receptor-interacting protein 2 (RIP2). RIP2(-/-) mice with E. coli infection displayed higher bacterial burden and reduced neutrophil recruitment and tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), macrophage inflammatory protein 2 (MIP-2), and CXCL5/LIX expression, along with attenuated histopathological changes in the lungs. Decreased IL-17A levels were observed, along with lower numbers of IL-17A-producing T cells, in RIP2(-/-) mice after infection. RIP2(-/-) mice also show reduced IL-6 and IL-23 levels in the lungs, along with decreased activation of STAT3 after infection. Furthermore, activation of NF-κB and mitogen-activated protein kinases (MAPKs) and expression of intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in the lungs of infected RIP2(-/-) mice were attenuated following infection. Although neutrophil mobilization to the blood was impaired in RIP2(-/-) mice following infection, the expression of CD62P, CD11a/18, CD11b, and CXCR2 on blood and lung neutrophils was not altered between infected wild-type (WT) and RIP2(-/-) mice. Thus, RIP2 contributes to neutrophil-dependent host defense against an extracellular Gram-negative pathogen via (i) IL-17A regulation and (ii) neutrophil mobilization to the blood.
authors.affiliation: Laboratory of Lung Biology, Department of Pathobiological Sciences and Center for Experimental Infectious Disease Research, Louisiana State University (LSU), Baton Rouge, Louisiana 708031, USA.
authors.forename: Theivanthiran
authors.initials: T
authors.lastname: Balamayooran
authors.forename: Sanjay
authors.initials: S
authors.lastname: Batra
authors.forename: Gayathriy
authors.initials: G
authors.lastname: Balamayooran
authors.forename: Shanshan
authors.initials: S
authors.lastname: Cai
authors.forename: Koichi S
authors.initials: KS
authors.lastname: Kobayashi
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
authors.forename: Samithamby
authors.initials: S
authors.lastname: Jeyaseelan
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D003713:Dendritic Cells / Q000378:metabolism; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000276:immunology*; D005786:Gene Expression Regulation / Q000276:immunology*; D018928:Immunity, Mucosal; D007249:Inflammation / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism*; D053759:Interleukin-23 / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000382:microbiology; D008171:Lung Diseases / Q000276:immunology / Q000382:microbiology*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D020929:Mitogen-Activated Protein Kinase Kinases; D016328:NF-kappa B / Q000378:metabolism; D009504:Neutrophils / Q000502:physiology; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D020381:Interleukin-17; D053759:Interleukin-23; D015850:Interleukin-6; D016169:Lymphocyte Function-Associated Antigen-1; D016328:NF-kappa B; D053475:Receptor-Interacting Protein Serine-Threonine Kinase 2; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; C506255:Ripk2 protein, mouse; D020929:Mitogen-Activated Protein Kinase Kinases