Hyperresponsiveness of mice deficient in plasma ... - Semantic Scholar

Hyperresponsiveness of mice deficient in plasma-secreted sphingomyelinase reveals its pivotal role in early phase of host response

Nayla Jbeily,1,2 Iris Suckert,1 Falk A. Gonnert, 1 Benedikt Acht,1 Clemens L. Bockmeyer,3 Sascha D. Grossmann,1 Markus F. Blaess,1 Anja Lueth, 4 Hans-Peter Deigner, 5 1 Michael Bauer,1 and Ralf A. Claus1‡from the Center of Sepsis Control and Care, Jena University

Hospital Jena, Germany 2 3 4

International Leibniz Research School, Jena, Germany

Institute for Pathology, Hannover Medical School MHH, Hannover, Germany

University of Potsdam, Institute of Nutritional Science, Dept. Nutritional Toxicology, Germany 5

University of Applied Science Furtwangen, Germany

Supplementary Data File

Legend to Table S1: Extract of transcripts differentially expressed in aSMase ko vs. wt littermates subsequent to polymicrobial peritonitis (315 transcripts in total during the late phase of host response). The functional summary is prepared using the GeneCards homepage of the Weizmann Institute of Science (www.genecards.org).

Table S1: Functional summary of differentially expressed transcripts

Gene symbol and nomenclature Ifitm2 Interferon-induced transmembrane protein 2 Pik3ap1 Phosphoinosite 3-Kinase adaptor protein 1 Seh1l Seh1-like protein Dusp16 Tgm2 Heatr1 Gpnmb Lcn2 Rcc1 Cxcl10 Pyroxd1 Snx10 Saa3 Ccar1 Bclaf1 Socs3 Wsb1 Map2k4

Dual-specifity phosphatase 16 Transglutaminase 2 HEAT repeat containing 1 glycoprotein NMB Lipocalin 2 Regulator of chromosome condensation 1 Chemkine, cxc motif, ligand 10 Pyridine nucleotide-disulphide oxidoreductase domain 1 Sorting nexin 10 Serum amyloid A1 Cell division cycle and apoptosis regulator 1 BCL2-associated transcription factor 1 Suppressor of cytokine signalling 3 WD-repeat and SOCS Boxcontaining protein 1 Mitigen-activated protein kinase kinase 4

Functional summary mediating cellular innate immunity, induced by IFN-γ activation of phosphoinositide 3-kinase (PI3K) Component of the Nup107-160 subcomplex of the nuclear pore complex for normal kinetochore microtubule attachment, mitotic progression and chromosome segregation. Dual specificity protein phosphatase involved in the inactivation of MAP kinases dephosphorylating MAPK10 Catalyzing the cross-linking of proteins and the conjugation of polyamines to proteins Involved in nucleolar processing of pre-18S ribosomal RNA and in ribosome biosynthesis Transmembrane glycoprotein with unknown function Iron-trafficking protein involved in multiple processes such as apoptosis, innate immunity and renal development. Guanine-nucleotide releasing factor that promotes the exchange of Ran-bound GDP by GTP. Involved in the regulation of onset of chromosome condensation in the S phase. Chemokine of the CXC subfamily and ligand for the receptor CXCR3; Binding of this protein to CXCR3 results in pleiotropic effects, including stimulation of monocytes, natural killer and T-cell migration, and modulation of adhesion molecule expression. Belongs to the class-I pyridine nucleotide-disulfide oxidoreductase family May be involved in several stages of intracellular trafficking and may play a role in endosome homeostasis. Major acute phase reactant. Apolipoprotein of the HDL complex Associates with components of the Mediator and p160 coactivator complexes that play a role as intermediaries transducing regulatory signals from upstream transcriptional activator proteins to basal transcription machinery at the core promoter. Death-promoting transcriptional repressor SOCS family proteins form part of a classical negative feedback system that regulates cytokine signal transduction. SOCS3 is involved in negative regulation of cytokines that signal through the JAK/STAT pathway. Probable substrate-recognition component of a SCF-like ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Essential component of the stress-activated protein kinase/c-Jun N-terminal kinase (SAP/JNK) signaling pathway, e.g. p38MAPK.

Table S1 (continued) Tbrg4 Csf3

Transforming growth factor beta regulator 4 Colony stimulating factor 3

Ccl7 Pim3 Nfkbiz

Chemokine, CC motif, ligand 7 Oncogene Pim3 NF-kB inhibitor zeta

Lilrb4

leukozyte immunoglobulin-like receptor, subfam B, member 4 Janus Kinase 3

Jak3 Tnfrsf9 Aoah Tnip1 Ms4a6d Il10

Gpr171 Tnfrsf1b Dusp11 Nupr1 Igsf6 Vasp Centd2 Prc1 Plaur

Tumor necrosis factor receptor superfamily, member 9 acyloxyacyl hydrolase (neutrophil) TNFAIP3-interacting protein 1 Membrane-spanning 4-domains, subfamA, member 6D Interleukin 10

G-protein-coupled recept. 171 Tumor necrosis factor receptor superfamily, member 1b Dual-specificity phosphatase 11 Nuclear protein, transcriptional regulator 1 Immunoglobulin superfamily 6 Vasodilatator-stimulated phosphoprotein Centaurin delta 2 protein regulating cytokinesis Plasminogen activator receptor, urokinase-type

cell cycle progression Cytokine controlling production, differentiation, and function of granulocytes and monocytes/macrophages. The active protein is found extracellularly. Chemotactic factor that attracts monocytes and eosinophils, but not neutrophils. Proto-oncogene with serine/threonine kinase activity that can prevent apoptosis, promote cell survival and protein translation. Involved in regulation of NF-kappa-B transcription factor complexes. Inhibits NF-kappa-B activity without affecting its nuclear translocation upon stimulation. Receptor for class I MHC antigens; involved in the down-regulation of the immune response and the development of tolerance Kinase involved in cytokine receptor-mediated intracellular signal transduction. It is predominantly expressed in immune cells and transduces a signal in response to its activation via tyrosine phosphorylation by interleukin receptors. Lymphocyte activation, activation of NF-κB modulating host inflammatory response to gram-negative bacteria by removal of the secondary (acyloxyacyl-linked) fatty acyl chains from the lipid A region of bacterial lipopolysaccharides inhibits TNF-induced NF-kappa-B-dependent gene expression may be involved in signal transduction as a component of a multimeric receptor complex Cytokine produced primarily by monocytes with pleiotropic effects in immunoregulation and inflammation, i.e. down-regulation of the expression of Th1 cytokines, MHC class II Ags, and costimulatory molecules on macrophages. This cytokine can block NF-κB activity, and is involved in the regulation of the JAK-STAT signaling pathway. Belongs to the G-protein coupled receptor 1 family with unknown function. Receptor with high affinity for TNF-alpha. This receptor mediates most of the metabolic effects of TNF-alpha. May participate in nuclear mRNA metabolism. Could participate in the response to proapoptotic stimuli and promotes cellular growth in a way that helps the tissue counteract diverse injuries. Memebrane protein, induction by TNF in dendritic cells and down regulation by phorbol myristate acetate (PMA) and ionomycin in monocytes actin-associated protein involved in a range of processes dependent on cytoskeleton remodeling and cell polarity such as platelet activation and cell migration. GTPase-activating protein that modulates actin cytoskeleton remodelling Key regulator of cytokinesis, essential for controlling the spatiotemporal formation of the midzone and successful cytokinesis. Receptor for urokinase plasminogen activator. Plays a role in localizing and promoting plasmin formation.

Table S1 (continued) Cyba

cytochrome B, alpha subunit

Ngp

Ccl3

solute carrier family 45, member 1 (=SLC45A1) Caspase 4, Apoptosis related cysteine protease Tumor-necrosis-factor-alphainduced protein 3 AT-rich interaction domaincontaing protein 3A Chemokine, CC Motif, ligand 3

Cd68

Macrophage antigen CD68

Mpo

Myeloperoxidase

Ccl4 Slfn2 Upp1

Chemokine, CC Motif, ligand 4 Schlafen 2 Uridine phosphorylase 1

Nfkbia

NFkB inhibitor alpha

Cd83 Ctsg

Cd83 antigen Cathepsin G

Ltb4r1

Leukotriene B4 receptor

Gpr84

G-protein coupled receptor 84

Pscd4 Ncf4

Cytohesin 4 Neutrophil cytosolic factor 4

Vav1

Oncogene VAV1

Casp4 Tnfaip3 Arid3a

encodes the light, alpha subunit of cytchrom b, proposed as a primary component of the microbicidal oxidase system of phagocytes. Critical component of the membrane-bound oxidase of phagocytes that generates superoxide. Associates with NOX3 to form a functional NADPH oxidase constitutively generating superoxide. Belongs to the glycoside-pentoside-hexuronide cation symporter transporter mediating glucose uptake along pH gradient. signal transduction pathways of apoptosis, necrosis and inflammation initiating the execution-phase of cell apoptosis. Ubiquitin-editing enzyme, ensuring the transient nature of inflammatory signaling pathways. Inhibitor of programmed cell death. Transcription factor which may be involved in the control of cell cycle progression and differentiation Monokine (syn. Macrophage inflammatory protein 1α) with inflammatory and chemokinetic properties binding to CCR1, CCR4 and CCR5. Lysosomal/endosomal-associated membrane glycoprotein highly expressed by human monocytes and tissue macrophages and binding to tissue- and organ-specific lectins or selectins. Function to clear cellular debris, promote phagocytosis, and mediate the recruitment and activation of macrophages. Rapid recirculation of CD68 from endosomes and lysosomes to the plasma membrane may allow macrophages to crawl over selectin-bearing substrates or other cells Lysosomal heme protein of the host defense system of polymorphonuclear leukocytes. It is responsible for microbicidal activity against a wide range of organisms. Monokine (syn. Macrophage inflammatory protein 1β) with inflammatory and chemokinetic properties. Binds to CCR5. belongs to the Schlafen family, ATP binding Catalyzes the reversible phosphorylytic cleavage of uridine and deoxyuridine to function as carbon and energy sources for nucleotide synthesis; induction by TNF-α Inhibits the activity of dimeric NFκB complexes through masking of their nuclear localization signals. On cellular stimulation by immune and proinflammatory responses, becomes phosphorylated promoting ubiquitination and degradation. May play a significant role in antigen presentation or the cellular interactions that follow lymphocyte activation Peptidase found in azurophil granules of neutrophilic polymorphonuclear leukocytes and may participate in the oxygen independent phagocytosis, killing and digestion of engulfed pathogens. Receptor found at their highest concentrations on myeloid cells, mast cells and macrophages for extracellular ATP > UTP and ADP. Is also a receptor for leukotriene B4, a potent chemoattractant involved in inflammation and immune response. Receptor for medium-chain free fatty acid (FFA) with carbon chain lengths of C9 to C14. May have important roles in processes from fatty acid metabolism to regulation of the immune system. Promotes guanine-nucleotide exchange on ARF1 and ARF5. Promotes the activation of ARF through replacement of GDP with GTP. Component of the NADPH-oxidase, a multicomponent enzyme system responsible for the oxidative burst generating reactive oxidant intermediates. It may be important for the assembly and/or activation of the NADPH-oxidase complex. Couples tyrosine kinase signals with the activation of the Rho/Rac GTPases, thus leading to cell differentiation and/or proliferation.

Table S1 (continued) Ebi3

Tlr7

Eppstein-Barr virus-induced gene 3 (=Il27β) Cell-divison cycle-associated protein 5 Toll-like receptor 7

Cybb

Cytochrome b, beta subunit

Trpm2

Transient receptor pot.l cation channel, subfam M, member 2 Lysozyme

Cdca5

Lyzs Timp2 Mapk3

Cd79a Man2b1 Hexa Tppp Hdac10 Mtdh Trem2

Tmem 134 Reps2

Tissue inhibitor of metalloproteinase 2 Mitogen-activated protein kinase 3 (p44ERK1)

CD79 A antigen mannosidase alpha, class 2b, member 1 Hexosaminidase A Tubulin polymerizationpromoting protein Histone deacetylase 10 Metadherin (= Astrocyte elevated gene 1, AEG1) Triggering receptor expressed on myeloid cells 2 Transmembrane protein 134 RALBP1-associated EPS domain-containing protein 2

Cytokine with pro- and anti-inflammatory properties with diverse effects on innate immune cells. Regulator of chromatid cohesion in mitosis stabilizing cohesin complex association with chromatin. Required for efficient DNA doublestranded break repair. Key component of innate and adaptive immunity. Toll-like receptors control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. TLR7 is a nucleotide-sensing TLR activated by single-stranded RNA. Beta subunit of cytochrome b which is has been proposed as a primary component of the microbicidal oxidase system of phagocytes enabling them to deliver activated oxygen into the phagocytic vacuole. Critical component of the membrane-bound oxidase of phagocytes that generates superoxide. Nonselective, voltage-independent cation channel mediating sodium and calcium ion influx in response to oxidative stress. Confers susceptibility to cell death following oxidative stress. Lysozymes have primarily bacteriolytic function cleaving peptidoglycans; those in tissues and body fluids are associated with the monocyte-macrophage system and enhance the activity of immunoagents. Complexes with metalloproteinases (such as collagenases) and irreversibly inactivates them by binding to their catalytic zinc cofactor. Serine/threonine kinase which acts as an essential component of the MAP kinase signal transduction pathway. Depending on the cellular context, the MAPK/ERK cascade mediates diverse biological functions such as cell growth, adhesion, survival and differentiation through the regulation of transcription, translation, cytoskeletal rearrangements. Moreover, the MAPK/ERK cascade is also involved in the regulation of the endosomal dynamics, including lysosome processing and endosome cycling. The B lymphocyte antigen receptor is a multimeric complex that includes the antigen-specific component, surface immunoglobulin. Lysosomal catabolism of N-linked carbohydrates released during glycoprotein turnover Alpha subunit of the lysosomal enzyme beta-hexosaminidase that, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. May play a role in the polymerization of tubulin into microtubules, microtubule bundling and the stabilization of existing microtubules, thus maintaining the integrity of the microtubule network. Deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation and cell cycle progression. Activates NFκB transcription factor mediated signalling. Induced by TNFα. May have a role in (chronic) inflammations and may stimulate production of constitutive rather than inflammatory chemokines and cytokines. Forms a receptor signaling complex with TYROBP and triggers activation of the immune responses in macrophages and dendritic cells. Transmembrane protein of unknown function. Cytoplamic protein involved in growth factor signaling through its influence on the Ral signaling pathway.

Table S1 (continued) Gstm6

Glutathione S-transferase, mu6

Surf6 Mgll

Surfeit 6 Monoglyceride lipase

Nfyb Aqp9

Nuclear transcription factor Y, beta Aquaporin 9

Nrg4

neuregulin 4

Alg8 Ephx1

Alg6, S. cerevisiae, homolog of Epoxide hydrolase 1, microsomal cytochrome P450, Subfamily XXVII, poplypeptide 1 Orosomucoid 2

Cyp27a1 Orm2 Aes Fn3k Vsig4

Aminoterminal enhancer of split Fructosamine 3-kinase V-Set and immunoglobulin Domains-containing protein 4

Member of µ-class of glutathione S-transferase functioning in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione. Nucleolar constitutive protein involved in ribosomal biosynthesis or assembly. Converting monoacylglycerides to free fatty acids and glycerol; Regulating the levels of fatty acids that serve as signaling molecules and promote cancer cell migration, invasion and tumor growth. Stimulates the transcription of various genes by recognizing and binding to a CCAAT motif in promoters, for example in type 1 collagen, albumin and beta-actin genes. Water-selective membrane channel allowing passage of a wide variety of noncharged solutes. It stimulates urea transport and osmotic water permeability, but may also play a role in specialized leukocyte functions such as immunological response and bactericidal activity. Low affinity ligand for a tyrosine kinase receptor resulting in ligand-stimulated tyrosine phosphorylation and activation of the ERBB receptors Glycosyltransferase adding the second glucose residue to the lipid-linked oligosaccharide precursor for N-linked glycosylation. Biotransformation enzyme that catalyzes the hydrolysis of arene and aliphatic epoxides to less reactive and more water soluble dihydrodiols by the trans addition of water. Monooxygenase which catalyzes many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This mitochondrial protein oxidizes cholesterol intermediates as part of the bile synthesis pathway. Functions as transport protein in circulating blood by binding various hydrophobic ligands influencing their distribution and availability. Appears to function in modulating the activity of the immune system during the acute-phase reaction. Acts as dominant repressor inhibiting NFκB regulated gene expression. May be required for the initiation and maintenance of the differentiated state. May initiate a process leading to the deglycation of fructoselysine and of glycated proteins. May play a role in the phosphorylation of glycated lysozyme. Phagocytic receptor, strong negative regulator of T-cell proliferation and IL2 production. Potent inhibitor of the alternative complement pathway convertases.