Proteomic profiling identifies novel inflammation-related plasma proteins associated with ischemic stroke outcome

Background The inflammatory response to cerebral ischemia is complex; however, most clinical studies of stroke outcome focus on a few selected proteins. We, therefore, aimed to profile a broad range of inflammation-related proteins to: identify proteins associated with ischemic stroke outcome that are independent of established clinical predictors; identify proteins subsets for outcome prediction; and perform sex and etiological subtype stratified analyses. Methods Acute-phase plasma levels of 65 inflammation-related proteins were measured in 534 ischemic stroke cases. Logistic regression was used to estimate associations to unfavorable 3-month functional outcome (modified Rankin Scale score > 2) and LASSO regressions to identify proteins with independent effects. Results Twenty proteins were associated with outcome in univariable models after correction for multiple testing (FDR < 0.05), and for 5 the association was independent of clinical variables, including stroke severity (TNFSF14 [LIGHT], OSM, SIRT2, STAMBP, and 4E-BP1). LASSO identified 9 proteins that could best separate favorable and unfavorable outcome with a predicted diagnostic accuracy (AUC) of 0.81; three associated with favorable (CCL25, TRAIL [TNFSF10], and Flt3L) and 6 with unfavorable outcome (CSF-1, EN-RAGE [S100A12], HGF, IL-6, OSM, and TNFSF14). Finally, we identified sex- and etiologic subtype-specific associations with the best discriminative ability achieved for cardioembolic, followed by cryptogenic stroke. Conclusions We identified candidate blood-based protein biomarkers for post-stroke functional outcome involved in, e.g., NLRP3 inflammasome regulation and signaling pathways, such as TNF, JAK/STAT, MAPK, and NF-κB. These proteins warrant further study for stroke outcome prediction as well as investigations into the putative causal role for stroke outcome. Supplementary Information The online version contains supplementary material available at 10.1186/s12974-023-02912-9.


IL-18
positive regulation of natural killer cell proliferation, positive regulation of activated T cell proliferation, positive regulation of NK T cell proliferation, positive regulation of T-helper 2 cell differentiation, positive regulation of T-helper 1 cell cytokine production, positive regulation of type II interferon production, positive regulation of interleukin-17 production, positive regulation of chemokine production, positive regulation of interleukin-13 production, positive regulation of granulocyte macrophage colonystimulating factor production, positive regulation of tissue remodeling, positive regulation of cold-induced thermogenesis, positive regulation of smooth muscle cell proliferation, positive regulation of transcription by RNA polymerase II, positive regulation of tyrosine phosphorylation of STAT protein, activation of protein kinase B activity, positive regulation of macrophage derived foam cell differentiation, positive regulation of NIK/NF-kappaB signaling, positive regulation of protein kinase B signaling, positive regulation of phosphatidylinositol 3-kinase signaling, MAPK cascade, NIK/NF-kappaB signaling, lipopolysaccharide-mediated signaling pathway, interleukin-18mediated signaling pathway, positive regulation of NF-kappaB transcription factor activity, negative regulation of myoblast differentiation, positive regulation of neuroinflammatory response, cell-cell signaling, natural killer cell activation, neutrophil activation, cell population proliferation, natural killer cell mediated cytotoxicity, cellular response to organic cyclic compound, establishment of skin barrier, angiogenesis, sleep, T-helper 1 type immune response, type 2 immune response, triglyceride homeostasis, cholesterol homeostasis, defense response to Gram-positive bacterium, inflammatory response IL-18R1 immune response, inflammatory response, natural killer cell activation, T-helper 1 cell differentiation, NIK/NF-kappaB signaling, interleukin-18-mediated signaling pathway, positive regulation of NIK/NF-kappaB signaling, positive regulation of NF-kappaB transcription factor activity, positive regulation of T-helper 1 cell cytokine production, positive regulation of type II interferon production, negative regulation of cold-induced thermogenesis

Chemokines CCL3
protein kinase B signaling, MAPK cascade, calcium-mediated signaling, lipopolysaccharide-mediated signaling pathway, chemokine-mediated signaling pathway, G protein-coupled receptor signaling pathway, positive regulation of natural killer cell chemotaxis, positive regulation of microglial cell migration, positive regulation of microglial cell activation, positive regulation of neuron apoptotic process, positive regulation of ERK1 and ERK2 cascade, positive regulation of protein kinase B signaling, positive regulation of calcium-mediated signaling, negative regulation of osteoclast differentiation, release of sequestered calcium ion into cytosol by sarcoplasmic reticulum, positive regulation of interleukin-1 beta production, positive regulation of tumor necrosis factor production, negative regulation of gene expression, negative regulation of bone mineralization, regulation of behavior, regulation of sensory perception of pain, positive regulation of calcium ion import, regulation of cell shape, cell-cell signaling, positive regulation of GTPase activity, neutrophil chemotaxis, eosinophil chemotaxis, monocyte chemotaxis, macrophage chemotaxis, T cell chemotaxis, astrocyte cell migration, eosinophil degranulation, cytoskeleton organization, cellular response to tumor necrosis factor, cellular response to interleukin-1, cellular response to type II interferon, cellular response to organic cyclic compound, osteoblast differentiation, intracellular calcium ion homeostasis, response to cholesterol, response to toxic substance, inflammatory response, negative regulation by host of viral transcription CCL4 establishment or maintenance of cell polarity, neutrophil chemotaxis, eosinophil chemotaxis, monocyte chemotaxis, lymphocyte chemotaxis, G protein-coupled receptor signaling pathway, chemokine-mediated signaling pathway, cell adhesion, cellular response to tumor necrosis factor, cellular response to interleukin-1, cellular response to type II interferon, cell-cell signaling, immune response, positive regulation of natural killer cell chemotaxis, positive regulation of ERK1 and ERK2 cascade, positive regulation of calcium-mediated signaling, positive regulation of calcium ion transport, positive regulation of GTPase activity, response to toxic substance, inflammatory response, response to virus, negative regulation by host of viral transcription CCL19 positive regulation of interleukin-1 beta production, positive regulation of tumor necrosis factor production, positive regulation of interleukin-12 production, positive regulation of glycoprotein biosynthetic process, positive regulation of JUN kinase activity, positive regulation of phosphatidylinositol 3-kinase activity, positive regulation of T cell proliferation, positive regulation of T-helper 1 cell differentiation, T cell costimulation, positive regulation of dendritic cell dendrite assembly, positive regulation of receptormediated endocytosis, positive regulation of NIK/NF-kappaB signaling, positive regulation of I-kappaB kinase/NF-kappaB signaling, positive regulation of JNK cascade, positive regulation of ERK1 and ERK2 cascade, positive regulation of protein kinase B signaling, positive regulation of neutrophil chemotaxis, positive regulation of dendritic cell antigen processing and presentation, release of sequestered calcium ion into cytosol, negative regulation of dendritic cell apoptotic process, G protein-coupled receptor signaling pathway, chemokine-mediated signaling pathway, positive regulation of GTPase activity, neutrophil chemotaxis, myeloid dendritic cell chemotaxis, monocyte chemotaxis, lymphocyte chemotaxis, immunological synapse formation, establishment of T cell polarity, cellular response to tumor necrosis factor, cellular response to interleukin-1, cellular response to type II interferon, cell maturation, mature conventional dendritic cell differentiation, cell communication, killing of cells of another organism, antimicrobial humoral immune response mediated by antimicrobial peptide, inflammatory response, cellular response to virus, response to prostaglandin E, response to nitric oxide, intracellular calcium ion homeostasis CCL20 neutrophil chemotaxis, monocyte chemotaxis, lymphocyte chemotaxis, thymocyte migration, G protein-coupled receptor signaling pathway, chemokine-mediated signaling pathway, calcium-mediated signaling using intracellular calcium source, cellular response to tumor necrosis factor, cellular response to interleukin-1, cellular response to type II interferon, cell-cell signaling, killing of cells of another organism, antimicrobial humoral immune response mediated by antimicrobial peptide, defense response to bacterium, inflammatory response, positive regulation of ERK1 and ERK2 cascade, positive regulation of T cell migration, positive regulation of GTPase activity CCL23 neutrophil chemotaxis, monocyte chemotaxis, lymphocyte chemotaxis, G proteincoupled receptor signaling pathway, chemokine-mediated signaling pathway, cellular response to tumor necrosis factor, cellular response to interleukin-1, cellular response to type II interferon, cell-cell signaling, immune response, inflammatory response, positive regulation of ERK1 and ERK2 cascade, negative regulation of cell population proliferation, positive regulation of GTPase activity, negative regulation of C-C chemokine binding, intracellular calcium ion homeostasis CCL25 neutrophil chemotaxis, monocyte chemotaxis, lymphocyte chemotaxis, chemokinemediated signaling pathway, G protein-coupled receptor signaling pathway, cellular response to tumor necrosis factor, cellular response to interleukin-1, cellular response to type II interferon, killing of cells of another organism, antimicrobial humoral immune response mediated by antimicrobial peptide, inflammatory response, positive regulation of ERK1 and ERK2 cascade, positive regulation of cell-matrix adhesion, negative regulation of leukocyte tethering or rolling, positive regulation of GTPase activity CCL28 antimicrobial humoral immune response mediated by antimicrobial peptide, response to nutrient, cytolysis in another organism, cell chemotaxis, positive regulation of cytosolic calcium ion concentration, negative regulation of leukocyte tethering or rolling, positive regulation of cell-matrix adhesion TNFB response to hypoxia, defense response to Gram-positive bacterium, response to nutrient, response to lipopolysaccharide, response to xenobiotic stimulus, humoral immune response, apoptotic process, signal transduction, cell-cell signaling, positive regulation of glial cell proliferation, positive regulation of apoptotic process, negative regulation of fibroblast proliferation, positive regulation of type II interferon production, positive regulation of humoral immune response mediated by circulating immunoglobulin, positive regulation of chronic inflammatory response to antigenic stimulus, lymph node development

Others
Beta-NGF nerve development, peripheral nervous system development, neuron projection morphogenesis, neuron apoptotic process, nerve growth factor signaling pathway, extrinsic apoptotic signaling pathway via death domain receptors, transmembrane receptor protein tyrosine kinase signaling pathway, modulation of chemical synaptic transmission, positive regulation of Ras protein signal transduction, positive regulation of neuron differentiation, positive regulation of collateral sprouting, positive regulation of peptidyl-serine phosphorylation, negative regulation of cell population proliferation, negative regulation of neuron apoptotic process, activation of cysteine-type endopeptidase activity involved in apoptotic process, positive regulation of gene expression, positive regulation of DNA binding, memory CASP-8 apoptotic process, pyroptosis, natural killer cell activation, T cell activation, B cell activation, TRAIL-activated apoptotic signaling pathway, cellular response to mechanical stimulus, cellular response to organic cyclic compound, macrophage differentiation, syncytiotrophoblast cell differentiation involved in labyrinthine layer development, execution phase of apoptosis, positive regulation of interleukin-1 beta production, activation of cysteine-type endopeptidase activity involved in apoptotic process, activation of cysteine-type endopeptidase activity, positive regulation of macrophage differentiation, positive regulation of I-kappaB kinase/NF-kappaB signaling, positive regulation of apoptotic process, positive regulation of neuron death, negative regulation of I-kappaB kinase/NF-kappaB signaling, regulation of tumor necrosis factor-mediated signaling pathway, negative regulation of necroptotic process, regulation of innate immune response, self proteolysis, proteolysis involved in protein catabolic process, response to tumor necrosis factor, response to lipopolysaccharide, response to estradiol, response to ethanol, response to antibiotic, response to cobalt ion, response to cold, angiogenesis, heart development CD40 protein kinase B signaling, immune response-regulating cell surface receptor signaling pathway, CD40 signaling pathway, TRIF-dependent toll-like receptor signaling pathway, positive regulation of transcription by RNA polymerase II, positive regulation of NF-kappaB transcription factor activity, positive regulation of isotype switching to IgG isotypes, positive regulation of tyrosine phosphorylation of STAT protein, positive regulation of MAP kinase activity, positive regulation of blood vessel endothelial cell migration, positive regulation of endothelial cell apoptotic process, positive regulation of I-kappaB kinase/NF-kappaB signaling, positive regulation of protein kinase C signaling, positive regulation of B cell proliferation, positive regulation of interleukin-12 production, positive regulation of angiogenesis, positive regulation of GTPase activity, cellular response to tumor necrosis factor, cellular response to interleukin-1, cellular response to mechanical stimulus, protein-containing complex assembly, B cell proliferation, platelet activation, B cell mediated immunity, intracellular calcium ion homeostasis, response to type II interferon, defense response to virus, defense response to protozoan, inflammatory response CDCP1 CST5 negative regulation of cysteine-type endopeptidase activity DNER central nervous system development, skeletal muscle fiber development, glial cell differentiation, Notch signaling pathway, synapse assembly, neuron migration, Notch receptor processing, endocytosis CCL11 neutrophil chemotaxis, eosinophil chemotaxis, mast cell chemotaxis, monocyte chemotaxis, lymphocyte chemotaxis, G protein-coupled receptor signaling pathway, chemokine-mediated signaling pathway, ERK1 and ERK2 cascade, protein phosphorylation, cell adhesion, cytoskeleton organization, positive regulation of actin filament polymerization, actin filament organization, cellular response to tumor necrosis factor, cellular response to interleukin-1, cellular response to type II interferon, killing of cells of another organism, antimicrobial humoral immune response mediated by antimicrobial peptide, response to interleukin-13, response to interleukin-4, chronic inflammatory response, response to virus, response to radiation, positive regulation of endothelial cell proliferation, positive regulation of cell migration, positive regulation of ERK1 and ERK2 cascade, negative regulation of neurogenesis, positive regulation of angiogenesis, regulation of cell shape, positive regulation of GTPase activity, intracellular calcium ion homeostasis, branching involved in mammary gland duct morphogenesis, learning or memory, mammary duct terminal end bud growth 4E-BP1 G1/S transition of mitotic cell cycle, TOR signaling, negative regulation of translational initiation, positive regulation of mitotic cell cycle Flt3L embryonic hemopoiesis, signal transduction, positive regulation of cell population proliferation CX3CL1 negative regulation of microglial cell activation, positive regulation of microglial cell migration, negative regulation of interleukin-1 alpha production, negative regulation of interleukin-1 beta production, negative regulation of tumor necrosis factor production, negative regulation of interleukin-6 production, positive regulation of transforming growth factor beta1 production, positive regulation of neuroblast proliferation, negative regulation of neuron migration, negative regulation of extrinsic apoptotic signaling pathway in absence of ligand, negative regulation of hippocampal neuron apoptotic process, negative regulation of glutamate receptor signaling negative regulation of cell-substrate adhesion, positive regulation of I-kappaB phosphorylation, positive regulation of transcription by RNA polymerase II, positive regulation of NF-kappaB transcription factor activity, positive regulation of smooth muscle cell proliferation, positive regulation of I-kappaB kinase/NF-kappaB signaling, positive regulation of ERK1 and ERK2 cascade, positive regulation of protein kinase B signaling, positive regulation of calcium-independent cell-cell adhesion, positive regulation of cellmatrix adhesion, positive regulation of neuron projection development, positive regulation of actin filament bundle assembly, positive regulation of release of sequestered calcium ion into cytosol, regulation of lipopolysaccharide-mediated signaling pathway, regulation of synaptic plasticity, G protein-coupled receptor signaling pathway, extrinsic apoptotic signaling pathway in absence of ligand, chemokine-mediated signaling pathway, positive regulation of inflammatory response, autocrine signaling, positive regulation of GTPase activity, neutrophil chemotaxis, eosinophil chemotaxis, monocyte chemotaxis, lymphocyte chemotaxis, leukocyte migration involved in inflammatory response, integrin activation, synapse pruning, cell-cell adhesion, leukocyte adhesive activation, microglial cell activation, cellular response to tumor necrosis factor, cellular response to interleukin-1, cellular response to type II interferon, neuron remodeling, microglial cell proliferation, immune response, positive chemotaxis, inflammatory response, response to ischemia, neuron cellular homeostasis, angiogenesis involved in wound healing GDNF sympathetic nervous system development, peripheral nervous system development, enteric nervous system development, nervous system development, postganglionic parasympathetic fiber development, metanephros development, embryonic organ development, dorsal spinal cord development, ureteric bud formation, organ induction, mesenchymal to epithelial transition involved in metanephros morphogenesis, branching involved in ureteric bud morphogenesis, mRNA stabilization, positive regulation of transcription by RNA polymerase II, negative regulation of extrinsic apoptotic signaling pathway in absence of ligand, negative regulation of neuron apoptotic process, positive regulation of cell population proliferation, positive regulation of mesenchymal to epithelial transition involved in metanephros morphogenesis, positive regulation of dopamine secretion, signal transduction, regulation of stem cell differentiation, regulation of semaphorin-plexin signaling pathway, positive regulation of ureteric bud formation, positive regulation of branching involved in ureteric bud morphogenesis, regulation of dopamine uptake involved in synaptic transmission, positive regulation of monooxygenase activity, postsynaptic membrane organization, commissural neuron axon guidance, neural crest cell migration, adult locomotory behavior, peristalsis HGF positive regulation of transcription by RNA polymerase II, positive regulation of DNA biosynthetic process, positive regulation of peptidyl-tyrosine phosphorylation, regulation of tau-protein kinase activity, negative regulation of peptidyl-serine phosphorylation, negative regulation of autophagy, positive regulation of neuron projection regeneration, positive regulation of MAPK cascade, positive regulation of 3-kinase signaling, positive regulation of osteoblast differentiation, positive regulation of cell migration, positive regulation of myelination, negative regulation of release of cytochrome c from mitochondria, regulation of p38MAPK cascade, negative regulation of hydrogen peroxide-mediated programmed cell death, negative regulation of extrinsic apoptotic signaling pathway via death domain receptors, negative regulation of cysteinetype endopeptidase activity involved in apoptotic process, hepatocyte growth factor receptor signaling pathway, negative regulation of interleukin-6 production, positive regulation of interleukin-10 production, positive regulation of angiogenesis, regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling, negative regulation of inflammatory response, liver development, animal organ regeneration, cell morphogenesis, epithelial to mesenchymal transition, skeletal muscle cell proliferation, myoblast proliferation, epithelial cell proliferation, cell chemotaxis, mitotic cell cycle, cellular response to hepatocyte growth factor stimulus IFN-gamma negative regulation of epithelial cell differentiation, positive regulation of neurogenesis, positive regulation of osteoclast differentiation, positive regulation of CD4-positive, CD25-positive, alpha-beta regulatory T cell differentiation involved in immune response, negative regulation of smooth muscle cell proliferation, negative regulation of tauprotein kinase activity, negative regulation of transcription by RNA polymerase II, positive regulation of cell population proliferation, positive regulation of protein serine/threonine kinase activity, positive regulation of tyrosine phosphorylation of STAT protein, positive regulation of peptidyl-serine phosphorylation of STAT protein, positive regulation of fructose 1,6-bisphosphate metabolic process, positive regulation of fructose 1,6bisphosphate 1-phosphatase activity, positive regulation of vitamin D biosynthetic process, positive regulation of nitric oxide biosynthetic process, positive regulation of glycolytic process, positive regulation of autophagy, positive regulation of membrane protein ectodomain proteolysis, positive regulation of cellular respiration, type II interferon-mediated signaling pathway, extrinsic apoptotic signaling pathway, receptor signaling pathway via JAK-STAT, positive regulation of iron ion import across plasma membrane, positive regulation of NMDA glutamate receptor activity, positive regulation of phagocytosis, positive regulation of protein-containing complex assembly, positive regulation of protein import into nucleus, positive regulation of protein localization to plasma membrane, positive regulation of exosomal secretion, positive regulation of smooth muscle cell apoptotic process, positive regulation of killing of cells of another organism, positive regulation of neuron death, positive regulation of epithelial cell migration, regulation of insulin secretion, positive regulation of tumor necrosis factor (ligand) superfamily member 11 production, positive regulation of tumor necrosis factor production, positive regulation of interleukin-1 beta production, positive regulation of interleukin-12 production, positive regulation of interleukin-23 production, positive regulation of interleukin-6 production, positive regulation of chemokine production, negative regulation of interleukin-17 production, negative regulation of amyloid-beta clearance, positive regulation of MHC class II biosynthetic process, positive regulation of nitric-oxide synthase biosynthetic process, positive regulation of protein deacetylation, positive regulation of amyloid-beta formation, positive regulation of inflammatory response, regulation of growth, regulation of protein ADP-ribosylation, positive regulation of calcidiol 1-monooxygenase activity, positive regulation of core promoter binding, apoptotic process, macrophage activation involved in immune response, microglial cell activation, astrocyte activation, macrophage differentiation, adaptive NT-3 nerve development, peripheral nervous system development, nervous system development, neuron projection morphogenesis, positive regulation of actin cytoskeleton reorganization, positive regulation of receptor internalization, positive regulation of cell population proliferation, activation of protein kinase B activity, positive regulation of MAP kinase activity, positive regulation of peptidyl-tyrosine phosphorylation, positive regulation of peptidyl-serine phosphorylation, positive regulation of cell migration, nerve growth factor signaling pathway, transmembrane receptor protein tyrosine kinase signaling pathway, negative regulation of neuron apoptotic process, modulation of chemical synaptic transmission, negative regulation of peptidyl-tyrosine phosphorylation, regulation of neuron differentiation, induction of positive chemotaxis, cell-cell signaling, activation of GTPase activity, memory OSM positive regulation of transcription by RNA polymerase II, positive regulation of tyrosine phosphorylation of STAT protein, positive regulation of peptidyl-serine phosphorylation, positive regulation of cell population proliferation, positive regulation of MAPK cascade, positive regulation of protein kinase B signaling, positive regulation of phosphatidylinositol 3-kinase signaling, positive regulation of cell division, negative regulation of cell population proliferation, negative regulation of hormone secretion, regulation of hematopoietic stem cell differentiation, oncostatin-M-mediated signaling pathway, positive regulation of interleukin-17 production, positive regulation of acute inflammatory response, regulation of growth, immune response OPG apoptotic process, signal transduction, extracellular matrix organization, response to estrogen, response to nutrient, response to arsenic-containing substance, response to xenobiotic stimulus, response to magnesium ion, negative regulation of osteoclast differentiation, negative regulation of bone resorption, negative regulation of odontogenesis of dentin-containing tooth, skeletal system development EN-RAGE defense response to fungus, antimicrobial humoral immune response mediated by antimicrobial peptide, innate immune response, defense response to bacterium, inflammatory response, killing of cells of another organism, neutrophil chemotaxis, monocyte chemotaxis, xenobiotic metabolic process, mast cell activation, positive regulation of I-kappaB kinase/NF-kappaB signaling, positive regulation of MAP kinase activity, positive regulation of NF-kappaB transcription factor activity, positive regulation of inflammatory response SLAMF1 natural killer cell proliferation, natural killer cell differentiation, myeloid dendritic cell activation involved in immune response, cell adhesion, leukocyte chemotaxis involved in inflammatory response, innate immune response, adaptive immune response, negative regulation of CD40 signaling pathway, positive regulation of JNK cascade, positive regulation of ERK1 and ERK2 cascade, positive regulation of activated T cell proliferation, positive regulation of dendritic cell chemotaxis, positive regulation of macrophage chemotaxis, regulation of vesicle fusion, negative regulation of T cell cytokine production, negative regulation of tumor necrosis factor production, negative regulation of interleukin-12 production, negative regulation of type II interferon production, negative regulation of interleukin-6 production, positive regulation of T-helper 1 cell cytokine production, positive regulation of type II interferon production, regulation of catalytic activity, phagocytosis SIRT2 cellular response to epinephrine stimulus, cellular response to molecule of bacterial origin, cellular response to oxidative stress, cellular response to hypoxia, negative regulation of transcription from RNA polymerase II promoter in response to hypoxia, cellular response to caloric restriction, cellular response to hepatocyte growth factor stimulus, innate immune response, response to redox state, protein kinase B signaling, phosphatidylinositol 3-kinase signaling, hepatocyte growth factor receptor signaling pathway, autophagy, cellular lipid catabolic process, rDNA heterochromatin formation, subtelomeric heterochromatin formation, NLRP3 inflammasome complex assembly, mitotic nuclear membrane reassembly, cell division, myelination in peripheral nervous system, meiotic cell cycle, positive regulation of transcription by RNA polymerase II, negative regulation of peptidyl-threonine phosphorylation, negative regulation of autophagy, negative regulation of reactive oxygen species metabolic process, positive regulation of oocyte maturation, positive regulation of attachment of spindle microtubules to kinetochore, positive regulation of meiotic nuclear division, positive regulation of execution phase of apoptosis, positive regulation of cell division, negative regulation of NLRP3 inflammasome complex assembly, negative regulation of oligodendrocyte progenitor proliferation, negative regulation of fat cell differentiation, regulation of exit from mitosis, regulation of myelination, positive regulation of proteasomal ubiquitin-dependent protein catabolic process involved in cellular response to hypoxia, negative regulation of protein catabolic process, negative regulation of striated muscle tissue development, negative regulation of defense response to bacterium, positive regulation of DNA binding, proteasome-mediated ubiquitindependent protein catabolic process, peptidyl-lysine deacetylation, tubulin deacetylation, histone H4 deacetylation, histone H3 deacetylation, substantia nigra development STAMBP positive regulation of cell population proliferation, negative regulation of Ras protein signal transduction, negative regulation of phosphatidylinositol 3-kinase signaling, negative regulation of hippocampal neuron apoptotic process, receptor signaling pathway via JAK-STAT, hippocampal neuron apoptotic process, mitotic cytokinesis, protein K63-linked deubiquitination SCF peptidyl-tyrosine phosphorylation, T cell proliferation, mast cell proliferation, embryonic hemopoiesis, ectopic germ cell programmed cell death, myeloid leukocyte differentiation, hematopoietic progenitor cell differentiation, mast cell apoptotic process, cell adhesion, Ras protein signal transduction, extrinsic apoptotic signaling pathway in absence of ligand, neural crest cell migration, melanocyte migration, mast cell migration, male gonad development, ovarian follicle development, positive regulation of melanocyte differentiation, positive regulation of myeloid leukocyte differentiation, positive regulation of hematopoietic progenitor cell differentiation, positive regulation of mast cell proliferation, positive regulation of T cell proliferation, positive regulation of hematopoietic stem cell proliferation, positive regulation of peptidyl-tyrosine phosphorylation, positive regulation of MAP kinase activity, positive regulation of Ras protein signal transduction, positive regulation of leukocyte migration, negative regulation of mast cell apoptotic process CD6 immunological synapse formation, lipopolysaccharide-mediated signaling pathway, heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules, positive regulation of T cell proliferation, positive regulation of protein phosphorylation, positive regulation of cytokine production involved in inflammatory response, response to lipopolysaccharide, innate immune response, acute inflammatory response to antigenic stimulus, adaptive immune response CD5 apoptotic signaling pathway, T cell costimulation, cell recognition TRANCE protein kinase B signaling, JNK cascade, ERK1 and ERK2 cascade, calcium-mediated signaling, I-kappaB kinase/NF-kappaB signaling, positive regulation of ERK1 and ERK2 cascade via TNFSF11-mediated signaling, positive regulation of transcription by RNA polymerase II, negative regulation of transcription by RNA polymerase II, positive regulation of NF-kappaB transcription factor activity, positive regulation of MAP kinase activity, positive regulation of I-kappaB kinase/NF-kappaB signaling, positive regulation of JNK cascade, positive regulation of protein kinase B signaling, positive regulation of corticotropin-releasing hormone secretion, positive regulation of osteoclast development, positive regulation of fever generation by positive regulation of prostaglandin secretion, positive regulation of T cell activation, positive regulation of homotypic cell-cell adhesion, positive regulation of gene expression, positive regulation of bone resorption, paracrine signaling, regulation of actin binding, osteoclast development, osteoclast differentiation, cellular response to leukemia inhibitory factor, mammary gland epithelial cell proliferation, osteoclast proliferation, monocyte chemotaxis, immune response, tooth eruption, mammary gland alveolus development, ossification, bone resorption, calcium ion homeostasis TRAIL apoptotic process, signal transduction, cell-cell signaling, positive regulation of extrinsic apoptotic signaling pathway, positive regulation of I-kappaB kinase/NF-kappaB signaling, positive regulation of release of cytochrome c from mitochondria, positive regulation of cysteine-type endopeptidase activity involved in apoptotic process, immune response, response to insulin, male gonad development TWEAK apoptotic process, extrinsic apoptotic signaling pathway, cell differentiation, endothelial cell migration, positive regulation of extrinsic apoptotic signaling pathway, positive regulation of endothelial cell proliferation, positive regulation of angiogenesis, positive regulation of protein catabolic process, immune response, angiogenesis TNFSF14 apoptotic process, T cell proliferation, signal transduction, cellular response to mechanical stimulus, T cell chemotaxis, T cell homeostasis, immune response, T cell costimulation, positive regulation of NIK/NF-kappaB signaling, positive regulation of myoblast differentiation, positive regulation of myoblast fusion, positive regulation of T cell chemotaxis TNFRSF9 apoptotic process, regulation of immature T cell proliferation in thymus, negative regulation of cell population proliferation

Table S2 :
Odds ratios and 95% confidence intervals for poor outcome 3-months after ischemic stroke per doubling of protein levels as compared to good outcome.Model 1: age, sex, day of blood draw and diabetes mellitus; Model 2: age, sex, day of blood draw, diabetes mellitus and stroke severity (maximum NIHSS score).OR, odds ratio

Table S3 :
Area under the receiver operating characteristics curve (AUC) for the LASSO model and for the individual proteins included in the model for all ischemic stroke and for sex-stratified analyses.

Table S3 ,
Continued: Area under the receiver operating characteristics curve (AUC) for the LASSO model and for the individual proteins included in the model for all ischemic stroke and for TOAST-stratified analyses.

Table S4 :
Odds ratios and 95% confidence intervals for poor outcome per doubling of protein levels as compared to good outcome stratified by sex (univariable).

Table S4 ,
Continued: Odds ratios and 95% confidence intervals for poor outcome per doubling of protein levels as compared to good outcome stratified by TOAST subtype (univariable).

Table S5 :
Odds ratios and 95% confidence intervals for poor outcome per doubling of protein levels as compared to good outcome in sensitivity analyses (univariable).