EphB2-dependent signaling promotes neuronal excitotoxicity and inflammation in the acute phase of ischemic stroke

Ernst, Anne-Sophie; Böhler, Laura-Inés; Hagenston, Anna M.; Hoffmann, Angelika; Heiland, Sabine; Sticht, Carsten; Bendszus, Martin; Hecker, Markus; Bading, Hilmar; Marti, Hugo H.; Korff, Thomas; Kunze, Reiner

doi:10.1186/s40478-019-0669-7

Acta Neuropathologica Communications

Table 1 KEGG pathway-Based gene set enrichment analyses (GSEA)

From: EphB2-dependent signaling promotes neuronal excitotoxicity and inflammation in the acute phase of ischemic stroke

Pathway Name	NES	NOM p-val	FDR q-val
Nicotine addiction	2.41	< 0.001	< 0.001
Glutamatergic synapse	2.08	< 0.001	0.001
Morphine addiction	2.03	< 0.001	0.001
Retrograde endocannabinoid signaling	1.97	< 0.001	0.001
GABAergic synapse	1.87	< 0.001	0.005
Axon guidance	1.83	< 0.001	0.007
Circadian entrainment	1.78	< 0.001	0.010
Calcium signaling pathway	1.77	< 0.001	0.011
Cocaine addiction	1.73	0.004	0.015
Salivary secretion	1.56	0.002	0.070
Neuroactive ligand-receptor interaction	1.55	< 0.001	0.072
Parkinson’s disease	1.53	0.002	0.079
Dopaminergic synapse	1.51	0.005	0.082
Platelet activation	− 1.50	0.003	0.048
Central carbon metabolism in cancer	− 1.50	0.020	0.047
Choline metabolism in cancer	−1.50	0.003	0.046
One carbon pool by folate	−1.50	0.042	0.046
Hypertrophic cardiomyopathy (HCM)	−1.51	0.012	0.043
TGF-beta signaling pathway	−1.53	0.014	0.036
Prolactin signaling pathway	−1.54	0.007	0.036
Inflammatory bowel disease (IBD)	−1.55	0.018	0.031
DNA replication	−1.55	0.026	0.031
NOD-like receptor signaling pathway	−1.55	0.011	0.031
Colorectal cancer	−1.55	0.009	0.031
Non-alcoholic fatty liver disease (NAFLD)	−1.56	0.002	0.029
Cell adhesion molecules (CAMs)	−1.58	0.002	0.027
Herpes simplex infection	−1.60	0.002	0.022
Viral myocarditis	−1.61	0.002	0.021
Melanoma	−1.61	0.007	0.021
Bladder cancer	−1.62	0.011	0.020
Galactose metabolism	−1.63	0.011	0.019
Adipocytokine signaling pathway	−1.63	0.002	0.018
Mineral absorption	−1.63	0.008	0.018
Acute myeloid leukemia	−1.64	0.011	0.017
Sphingolipid signaling pathway	−1.65	< 0.001	0.015
MAPK signaling pathway	−1.67	< 0.001	0.013
Pathways in cancer	−1.67	< 0.001	0.013
Hepatitis C	−1.68	< 0.001	0.012
Biosynthesis of amino acids	−1.69	< 0.001	0.011
Protein digestion and absorption	−1.72	< 0.001	0.008
Estrogen signaling pathway	−1.72	< 0.001	0.008
Fc epsilon RI signaling pathway	−1.74	< 0.001	0.007
Transcriptional misregulation in cancer	−1.74	< 0.001	0.007
Natural killer cell mediated cytotoxicity	−1.74	< 0.001	0.007
Glioma	−1.74	< 0.001	0.007
Regulation of actin cytoskeleton	−1.74	< 0.001	0.007
Bacterial invasion of epithelial cells	−1.75	0.002	0.007
Cell cycle	−1.76	< 0.001	0.006
Chemokine signaling pathway	−1.76	< 0.001	0.006
Arginine and proline metabolism	−1.77	< 0.001	0.005
Measles	−1.77	< 0.001	0.006
Pancreatic cancer	−1.78	< 0.001	0.005
Fc gamma R-mediated phagocytosis	−1.79	< 0.001	0.005
HTLV-I infection	−1.79	< 0.001	0.004
FoxO signaling pathway	−1.80	< 0.001	0.004
Chronic myeloid leukemia	−1.82	< 0.001	0.003
Prostate cancer	−1.84	< 0.001	0.003
MicroRNAs in cancer	−1.84	< 0.001	0.003
Hepatitis B	−1.85	< 0.001	0.002
Salmonella infection	−1.85	0.002	0.002
Protein processing in endoplasmic reticulum	−1.87	< 0.001	0.002
VEGF signaling pathway	−1.87	< 0.001	0.002
Epstein-Barr virus infection	−1.87	< 0.001	0.002
Influenza A	−1.88	< 0.001	0.002
Spliceosome	−1.92	< 0.001	0.001
Phagosome	−1.93	< 0.001	0.001
Tuberculosis	−1.93	< 0.001	0.001
Chagas disease (American trypanosomiasis)	−1.94	< 0.001	0.001
Hematopoietic cell lineage	−1.96	< 0.001	0.001
Toll-like receptor signaling pathway	−1.97	< 0.001	0.001
Jak-STAT signaling pathway	−1.97	< 0.001	0.001
PI3K-Akt signaling pathway	−1.97	< 0.001	0.001
Proteasome	−1.98	< 0.001	0.001
Apoptosis	−2.00	< 0.001	0.001
Rheumatoid arthritis	−2.00	< 0.001	0.001
Amoebiasis	−2.00	< 0.001	0.001
Antigen processing and presentation	−2.00	< 0.001	0.001
Pertussis	−2.05	< 0.001	< 0.001
Malaria	−2.06	< 0.001	< 0.001
Staphylococcus aureus infection	−2.06	< 0.001	< 0.001
Legionellosis	−2.06	< 0.001	< 0.001
Osteoclast differentiation	−2.07	< 0.001	< 0.001
B cell receptor signaling pathway	−2.07	< 0.001	< 0.001
HIF-1 signaling pathway	−2.08	< 0.001	< 0.001
Leishmaniasis	−2.11	< 0.001	< 0.001
Proteoglycans in cancer	−2.12	< 0.001	< 0.001
p53 signaling pathway	−2.13	< 0.001	< 0.001
Leukocyte transendothelial migration	−2.15	< 0.001	< 0.001
Complement and coagulation cascades	−2.16	< 0.001	< 0.001
TNF signaling pathway	−2.17	< 0.001	< 0.001
NF-kappa B signaling pathway	−2.20	< 0.001	< 0.001
Toxoplasmosis	−2.22	< 0.001	< 0.001
Cytokine-cytokine receptor interaction	−2.23	< 0.001	< 0.001
Small cell lung cancer	−2.27	< 0.001	< 0.001
Focal adhesion	−2.29	< 0.001	< 0.001
ECM-receptor interaction	−2.46	< 0.001	< 0.001

Ephb2^−/− and WT mice (n = 3) were subjected to 60 min MCAO followed by 48 h reperfusion. Total RNA was extracted from ipsilesional brain tissue and processed for DNA microarray analysis (GeneChip Mouse Gene 2.0 ST; Affymetrix, Santa Clara, CA, USA). The table lists all significantly UP and DOWN-regulated gene sets comparing Ephb2^−/− versus WT matching the following criteria for selection: ≥1.5- or ≤ 1.5-fold regulation (log₂-fold), p < 0.05 (ANOVA), FDR < 0.1. NES: normalized enrichment score; FDR: false discovery rate

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