Molecular Mechanisms Underlying Neuroinflammation Elicited by Occupational Injuries and Toxicants

Abstract

Occupational injuries and toxicant exposures lead to the development of neuroinflammation by activating distinct mechanistic signaling cascades that ultimately culminate in the disruption of neuronal function leading to neurological and neurodegenerative disorders. The entry of toxicants into the brain causes the subsequent activation of glial cells, a response known as 'reactive gliosis'. Reactive glial cells secrete a wide variety of signaling molecules in response to neuronal perturbations and thus play a crucial role in the progression and regulation of central nervous system (CNS) injury. In parallel, the roles of protein phosphorylation and cell signaling in eliciting neuroinflammation are evolving. However, there is limited understanding of the molecular underpinnings associated with toxicant- or occupational injury-mediated neuroinflammation, gliosis, and neurological outcomes. The activation of signaling molecules has biological significance, including the promotion or inhibition of disease mechanisms. Nevertheless, the regulatory mechanisms of synergism or antagonism among intracellular signaling pathways remain elusive. This review highlights the research focusing on the direct interaction between the immune system and the toxicant- or occupational injury-induced gliosis. Specifically, the role of occupational injuries, e.g., trips, slips, and falls resulting in traumatic brain injury, and occupational toxicants, e.g., volatile organic compounds, metals, and nanoparticles/nanomaterials in the development of neuroinflammation and neurological or neurodegenerative diseases are highlighted. Further, this review recapitulates the recent advancement related to the characterization of the molecular mechanisms comprising protein phosphorylation and cell signaling, culminating in neuroinflammation.

Keywords: Alzheimer’s disease; Parkinson’s disease; amyotrophic lateral sclerosis; astrocytes; cell signaling; gliosis; hydrocarbons; immune response; inflammation; metals; microglia; multiple sclerosis; nanoparticles; neurodegenerative diseases; neuroinflammation; neurological disorders; occupational injury; traumatic brain injury; workplace toxicants.

Figure 1

Inflammatory mechanism in traumatic brain injury. Schematic representation of the molecular mechanisms associated with glia-mediated functional interactions and systematic perturbations within the CNS to induce neuroinflammation in traumatic brain injury. The endothelial cells form the inner lining of the blood vessel with pericytes enveloping the surface of the vasculature forming tight junctions to maintain the BBB integrity. Upon insult, neurons release danger/damage signals that cause activation of neighboring glial cells. M1 microglia (proinflammatory phenotype, neurotoxic) release various proinflammatory mediators including free radicals, cytokines, and chemokines that further stimulate other glial cells and collectively contribute to exacerbating the neuronal injury/damage. M2 microglial cells (anti-inflammatory phenotype, neuroprotective) can polarize to an M1 state and release proinflammatory mediators in the presence of increased levels of NOX, ROS, NO, and IL33 released by M1 microglia and/or astrocytes and thereby augment the neuroinflammatory and neuronal injury process leading to synaptic dysfunction, neuronal injury, and neuronal death. Astrocytes respond by releasing proinflammatory mediators including free radicals, cytokines, and chemokines, which further contribute to enhancing the endothelial permeability, disrupting BBB integrity, and allowing for infiltration of peripheral immune cells, events that further intensify inflammation and neuronal injury. Feedback regulation of NOX or its inhibition causes M1 microglia to polarize to the M2 state (anti-inflammatory phenotype), which downregulates M1 functions and promotes regulation of neuroinflammation and neurorepair by releasing anti-inflammatory mediators, e.g., cytokines, neurotrophic, and growth factors. Mediators released by specific neural cell types (neuron, astrocyte, microglia, or oligodendrocyte) are listed adjacent to each cell type in similar colored text. Curved arrows indicate the direction of signal flow between various neural cells for the inflammation activation process. Red curved arrows show the directional flow of danger/damage signals from neurons to glial cells (astroglia, microglia, oligodendroglia); blue curved arrows show the flow of proinflammatory signals from astrocytes and M1 microglia towards distressed neurons; green curved arrows show the flow of neurotrophic signals from M2 microglia and oligodendroglia towards the distressed neurons as a neuroprotective/neurorescue endeavor; black curved arrows show the directional crosstalk among various glial cells to mount a glial response to neuronal injury/damage. ↑, increase; ↓, decrease; ARG1, arginase 1; ATP, adenosine triphosphate; BBB, blood-brain barrier; CCL2, C-C motif chemokine ligand 2 (also referred to as MCP1, monocyte chemoattractant protein 1); CCL3, C-C motif chemokine ligand 3; CCL5, C-C motif chemokine ligand 5; CCL11, C-C motif chemokine ligand 11; CD68, CD68 molecule; CD163, CD163 molecule; CHIL3, chitinase-like protein 3 (also referred to as YM1); CXCL1, C-X-C motif chemokine ligand 1; CXCL4, C-X-C motif chemokine ligand 4; ET1, endothelin 1; FGF2, fibroblast growth factor 2; FIZZ1, found in inflammatory zone 1; HGF, hepatocyte growth factor; HMGB1, high-mobility group box 1; HSP, heat shock proteins; IL1B, interleukin 1 beta; IL4, interleukin 4; IL6, interleukin 6; IL10, interleukin 10; IL12, interleukin 12; IL33, interleukin 33; MMP9, matrix metalloproteinase 9; MRC1, mannose receptor C-type 1 (also referred to as CD206); NO, nitric oxide; NOS2, nitric oxide synthase 2 (inducible nitric oxide synthase); NOX, NADPH oxidase 1; PGE2, prostaglandin E2; PTGS2, prostaglandin-endoperoxide synthase 2 (also referred to as COX2, cyclooxygenase 2); ROS, reactive oxygen species; S100B, calcium binding protein B; TGFB, transforming growth factor beta; TGFB2, transforming growth factor beta 2; TNFA, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor.

Figure 2

Inflammatory cascade in Alzheimer’s disease. Schematic representation of the molecular mechanisms associated with glia-mediated functional interactions and systematic perturbations within the CNS to induce neuroinflammation in Alzheimer’s disease. The endothelial cells form the inner lining of the blood vessel with pericytes enveloping the surface of the vasculature forming tight junctions to maintain the BBB integrity. Upon insult, the augmented production and release, as well as impaired clearance of Aβ and Tau fibrils sustains chronic activation of the primed microglia resulting in the production and release of proinflammatory mediators including free radicals, cytokines and chemokines, thereby affecting the resident CNS cells (astrocytes, oligodendrocytes, and neurons) and leading to Aβ and Tau aggregation. M1 microglia (proinflammatory phenotype, neurotoxic) release various proinflammatory mediators including free radicals, cytokines, and chemokines that further stimulate other glial cells and collectively contribute to exacerbating the neuronal injury/damage. M2 microglial cells (anti-inflammatory phenotype, neuroprotective) can polarize to an M1 state and release proinflammatory mediators in the presence of increased levels of NOX, ROS, NO, and IL33 released by M1 microglia and/or astrocytes and thereby augment the neuroinflammatory and neuronal injury process leading to synaptic dysfunction, neuronal injury, and neuronal death. Astrocytes respond by releasing proinflammatory mediators including free radicals, cytokines, and chemokines, which further contribute to enhancing the endothelial permeability, disrupting BBB integrity, and allowing for infiltration of peripheral immune cells, events that further intensify inflammation and neuronal injury. Feedback regulation of NOX or its inhibition causes M1 microglia to polarize to the M2 state (anti-inflammatory phenotype), which downregulates M1 functions and promotes regulation of neuroinflammation and neurorepair by releasing anti-inflammatory mediators such as cytokines, neurotrophic, and growth factors. Mediators released by specific neural cell types (neuron, astrocyte, microglia, or oligodendrocyte) are listed adjacent to each cell type in similar colored text. Curved arrows indicate the direction of signal flow between various neural cells for the inflammation activation process. Red curved arrows show the directional flow of danger/damage signals from neurons to glial cells (astroglia, microglia, oligodendroglia); blue curved arrows show the flow of proinflammatory signals from astrocytes and M1 microglia towards distressed neurons; green curved arrows show the flow of neurotrophic signals from M2 microglia and oligodendroglia towards the distressed neurons as a neuroprotective/neurorescue endeavor; black curved arrows show the directional crosstalk among various glial cells to mount a glial response to neuronal injury/damage. ↑, increase; ↓, decrease; Aβ, beta amyloid; APP, amyloid precursor protein; ATP, adenosine triphosphate; BBB, blood-brain barrier; BDNF, brain-derived neurotrophic factor; CCL2, C-C motif chemokine ligand 2 (also referred to as MCP1, monocyte chemoattractant protein 1); CCL3, C-C motif chemokine ligand 3; CCL5, C-C motif chemokine ligand 5; CCL11, C-C motif chemokine ligand 11; CCR3, C-C motif chemokine receptor 3; CCR5, C-C motif chemokine receptor 5; 1; CXCL1, C-X-C motif chemokine ligand 1; CXCL10, C-X-C motif chemokine ligand 10; FGF, fibroblast growth factor; FGF2, fibroblast growth factor 2; FIZZ1, found in inflammatory zone 1; HGF, hepatocyte growth factor; HSP, heat shock proteins; IFNA, interferon alpha; IFNB, interferon beta; IFNG, interferon gamma; IGF1, insulin-like growth factor 1; IL1B, interleukin 1 beta; IL6, interleukin 6; IL10, interleukin 10; IL12, interleukin 12; IL33, interleukin 33; NGF, nerve growth factor; NO, nitric oxide; NOS2, nitric oxide synthase 2 (inducible nitric oxide synthase); NOX, NADPH oxidase 1; PDGF, platelet-derived growth factor; PGE2, prostaglandin E2; PTGS2, prostaglandin-endoperoxide synthase 2 (also referred to as COX2, cyclooxygenase 2); ROS, reactive oxygen species; S100B calcium binding protein B; TGFB1, transforming growth factor beta 1; TGFB2, transforming growth factor beta 2; TNFA, tumor necrosis factor alpha; VEGF, vascular endothelial growth factor.

Figure 3

Inflammatory cascade in Parkinson’s disease. Schematic representation of the molecular mechanisms associated with glia-mediated functional interactions and systematic perturbations within the CNS to induce neuroinflammation in Parkinson’s disease. The endothelial cells form the inner lining of the blood vessel with pericytes enveloping the surface of the vasculature forming tight junctions to maintain the BBB integrity. Upon insult, the augmented production and release, as well as impaired clearance of αSYN (SNCA) sustains chronic activation of the primed microglia resulting in the production and release of proinflammatory mediators including free radicals, cytokines and chemokines, thereby affecting the resident CNS cells (astrocytes, oligodendrocytes, and neurons) and leading to αSYN (SNCA) aggregation, neuronal injury and Lewy body formation. M1 microglia (proinflammatory phenotype, neurotoxic) release various proinflammatory mediators, including free radicals, cytokines, and chemokines that further stimulate other glial cells and collectively contribute to exacerbating neuronal injury/damage. M2 microglial cells (anti-inflammatory phenotype, neuroprotective) can polarize to an M1 state and release proinflammatory mediators in the presence of increased levels of NOX, ROS, NO, and IL33 released by M1 microglia and/or astrocytes and thereby augment the neuroinflammatory and neuronal injury process leading to synaptic dysfunction, neuronal injury, and neuronal death. Astrocytes respond by releasing proinflammatory mediators, including free radicals, cytokines, and chemokines, which further contribute to enhancing endothelial permeability, disrupting BBB integrity, and allowing for infiltration of peripheral immune cells, events that further intensify inflammation and neuronal injury. Feedback regulation of NOX or its inhibition causes M1 microglia to polarize to the M2 state (anti-inflammatory phenotype), which downregulates M1 functions and promotes regulation of neuroinflammation and neurorepair by releasing anti-inflammatory mediators such as cytokines, neurotrophic, and growth factors. Mediators released by specific neural cell types (neuron, astrocyte, microglia, or oligodendrocyte) are listed adjacent to each cell type in similar colored text. Curved arrows indicate the direction of signal flow between various neural cells for the inflammation activation process. Red curved arrows show the directional flow of danger/damage signals from neurons to glial cells (astroglia, microglia, oligodendroglia); blue curved arrows show the flow of proinflammatory signals from astrocytes and M1 microglia towards distressed neurons; green curved arrows show the flow of neurotrophic signals from M2 microglia and oligodendroglia towards the distressed neurons as a neuroprotective/neurorescue endeavor; black curved arrows show the directional crosstalk among various glial cells to mount a glial response to neuronal injury/damage. ↑, increase; ↓, decrease; ATP, adenosine triphosphate; BBB, blood-brain barrier; CCL2, C-C motif chemokine ligand 2 (also referred to as MCP1, monocyte chemoattractant protein 1); CCL3, C-C motif chemokine ligand 3; CCL5, C-C motif chemokine ligand 5; CCL11, C-C motif chemokine ligand 11; CSF1, colony-stimulating factor 1; FAS, Fas cell surface death receptor; FASLG, Fas ligand; FGF2, fibroblast growth factor 2; HGF, hepatocyte growth factor; HMGB1, high-mobility group box 1; IFNA, interferon alpha; IFNB, interferon beta; IFNG, interferon gamma; IGF1, insulin-like growth factor 1; IL1B, interleukin 1 beta; IL6, interleukin 6; IL10, interleukin 10; IL33, interleukin 33;NO, nitric oxide; NOS2, nitric oxide synthase 2 (inducible nitric oxide synthase); NOX, NADPH oxidase 1; PGE2, prostaglandin E2; PTGS2, prostaglandin-endoperoxide synthase 2 (also referred to as COX2, cyclooxygenase 2); ROS, reactive oxygen species; αSYN/SNCA, alpha synuclein; TGFB2, transforming growth factor beta 2; TNFA, tumor necrosis factor alpha.

Figure 4

Inflammatory cascade in Amyotrophic Lateral Sclerosis. Schematic representation of the molecular mechanisms associated with glia-mediated functional interactions and systematic perturbations within the CNS to induce neuroinflammation in Parkinson’s disease. The endothelial cells form the inner lining of the blood vessel with pericytes enveloping the surface of the vasculature forming tight junctions to maintain the BBB integrity. Upon insult, the augmented production and release, as well as impaired clearance of mutant SOD1 trimers, TDP43, and ubiquitin aggregates sustains chronic activation of the primed microglia resulting in the production and release of proinflammatory mediators, including free radicals, cytokines, and chemokines, thereby affecting the resident CNS cells (astrocytes, oligodendrocytes, and neurons) and leading to disruption of nuclear-cytoplasmic transport, ubiquitination and accumulation of TDP43 in the cytoplasm, aggregation of SODI trimers, and subsequent neuronal injury/damage. M1 microglia (proinflammatory phenotype, neurotoxic) release various proinflammatory mediators including free radicals, cytokines and chemokines that further stimulate other glial cells and collectively contribute to exacerbating the neuronal injury/damage. M2 microglial cells (anti-inflammatory phenotype, neuroprotective) can polarize to an M1 state and release proinflammatory mediators in the presence of increased levels of NOX, ROS, NO, and IL33 released by M1 microglia and/or astrocytes and thereby augment the neuroinflammatory and neuronal injury process leading to synaptic dysfunction, neuronal injury, and neuronal death. Astrocytes respond by releasing proinflammatory mediators, including free radicals, cytokines, and chemokines, which further contribute to enhancing the endothelial permeability, disrupting BBB integrity, and allowing for infiltration of peripheral immune cells, events that further intensify inflammation and neuronal injury. Feedback regulation of NOX or its inhibition causes M1 microglia to polarize to the M2 state (anti-inflammatory phenotype), which downregulates M1 functions and promotes regulation of neuroinflammation and neurorepair by releasing anti-inflammatory mediators, e.g., cytokines, neurotrophic, and growth factors. Mediators released by specific neural cell types (neuron, astrocyte, microglia or oligodendrocyte) are listed adjacent to each cell type in similar colored text. Curved arrows indicate the direction of signal flow between various neural cells for the inflammation activation process. Red curved arrows show the directional flow of danger/damage signals from neurons to glial cells (astroglia, microglia, oligodendroglia); blue curved arrows show the flow of proinflammatory signals from astrocytes and M1 microglia towards distressed neurons; green curved arrows show the flow of neurotrophic signals from M2 microglia and oligodendroglia towards the distressed neurons as a neuroprotective/neurorescue endeavor; black curved arrows show the directional crosstalk among various glial cells to mount a glial response to neuronal injury/damage. ↑, increase; ↓, decrease; ATP, adenosine triphosphate; BBB, blood-brain barrier; FAS, Fas cell surface death receptor; FASLG, Fas ligand; IL1B, interleukin 1 beta; IL6, interleukin 6; IL33, interleukin 33; NO, nitric oxide; NOS2, nitric oxide synthase 2 (inducible nitric oxide synthase); NOX, NADPH oxidase 1; PGE2, prostaglandin E2; PTGS2, prostaglandin-endoperoxide synthase 2 (also referred to as COX2, cyclooxygenase 2); ROS, reactive oxygen species; SOD1, superoxide dismutase 1; TNFA, tumor necrosis factor alpha.

Figure 5

Inflammatory cascade in Multiple Sclerosis. Schematic representation of the molecular mechanisms associated with glia-mediated functional interactions and systematic perturbations within the CNS to induce neuroinflammation in Multiple Sclerosis. The multifocal inflammatory demyelination of the white matter is driven largely by an inflammatory process besides an autoimmune component that involves innate and adaptive (B and T lymphocytes) immune cells. Various subtypes of myeloid cells are also critical for the pathogenic implications and the blood-derived monocytes represent the highest fraction of infiltrating peripheral cells into the CNS that undergo transformation into monocyte-derived inflammatory phagocytes (macrophages or dendritic cells) leading to neuronal damage. The endothelial cells form the inner lining of the blood vessel with pericytes enveloping the surface of the vasculature forming tight junctions to maintain the BBB integrity. Disruption of the BBB integrity further facilitates the infiltration of autoreactive immune cells into the CNS. Microglia serve as antigen presenting cells and present the myelin antigen to infiltrating B and T-cells, thereby exacerbating the neuroinflammatory cascade. M1 microglia (proinflammatory phenotype, neurotoxic) release various proinflammatory mediators, including free radicals, cytokines, and chemokines that further stimulate other glial cells, thus perpetuating a self-destructive environment that collectively contributes to exacerbating the neuronal injury/damage. M2 microglial cells (anti-inflammatory phenotype, neuroprotective) can polarize to an M1 state and release proinflammatory mediators in the presence of increased levels of NOX, ROS, NO, and IL33 released by M1 microglia and/or astrocytes and thereby augment the neuroinflammatory and neuronal injury process leading to synaptic dysfunction, neuronal injury, and neuronal death. Astrocytes respond by releasing proinflammatory mediators, including free radicals, cytokines, and chemokines, which further contribute to enhancing the endothelial permeability, disrupting BBB integrity, and allowing for infiltration of peripheral immune cells, events that further intensify inflammation and neuronal injury. Feedback regulation of NOX or its inhibition causes M1 microglia to polarize to the M2 state (anti-inflammatory phenotype), which downregulates M1 functions and promotes regulation of neuroinflammation and neurorepair by releasing anti-inflammatory mediators, e.g., cytokines, neurotrophic, and growth factors. Mediators released by specific neural cell types (neuron, astrocyte, microglia or oligodendrocyte) are listed adjacent to each cell type in similar colored text. Curved arrows indicate the direction of signal flow between various neural cells for the inflammation activation process. Red curved arrows show the directional flow of danger/damage signals from neurons to glial cells (astroglia, microglia, oligodendroglia); blue curved arrows show the flow of proinflammatory signals from astrocytes and M1 microglia towards distressed neurons; green curved arrows show the flow of neurotrophic signals from M2 microglia and oligodendroglia towards the distressed neurons as a neuroprotective/neurorescue endeavor; black curved arrows show the directional crosstalk among various glial cells to mount a glial response to neuronal injury/damage. ↑, increase; ↓, decrease; BBB, blood-brain barrier; CCL2, C-C motif chemokine ligand 2 (also referred to as MCP1, monocyte chemoattractant protein 1); CCL3, C-C motif chemokine ligand 3; CCL5, C-C motif chemokine ligand 5; CCL11, C-C motif chemokine ligand 11; CXCL12, C-X-C motif chemokine ligand 12; CX3CR1, C-X3-C motif chemokine receptor 1 (also referred to as fractalkine receptor); FAS, Fas cell surface death receptor; FASLG, Fas ligand; IFNG, interferon gamma; IL1B, interleukin 1 beta; IL6, interleukin 6; IL23, interleukin 23; IL33, interleukin 33; MHC, major histocompatibility complex; NO, nitric oxide; NOS2, nitric oxide synthase 2 (inducible nitric oxide synthase); NOX, NADPH oxidase 1; ROS, reactive oxygen species; SPP1, secreted phosphoprotein 1; TGFB, transforming growth factor beta; TNFA, tumor necrosis factor alpha; TNFSF13B, TNF superfamily member 13b; TREM2, triggering receptor expressed on myeloid cells 2.

Figure 6

NF-κB signaling in neuroinflammatory response. Schematic representation depicts activation and regulation of NF-κB signaling pathways by various inflammatory ligands. NF-κB activation is initiated when ligands stimulate various cell-surface receptors, e.g., TLR2, IL1R, TNFR or RAGE. Upon stimulation, TLRs and IL1R assembles the cytoplasmic MYD88 complex, which recruits IRAK and TAK1. Stimulation of TNFR recruits TRAFs. TAK1 and TRAFs activate the downstream kinase IKK, which in turn phosphorylate the NF-κB inhibitor IκBα, leading to ubiquitin-dependent IκBα degradation and NF-κB activation. Once activated, TRAFs function as an E3 ubiquitin ligase that catalyzes the synthesis of K63-linked polyubiquitin chains conjugated to itself, NEMO. A complex signal transduction process then starts as soon as TNFRs are activated. IKK is ultimately triggered and leads to the phosphorylation of IκB, which results in IκB ubiquitination and degradation. When IκB is degraded, the remaining NF-κB dimer (e.g., p65/p50 or p50/p50 subunit or their putative combination) translocates to the nucleus, which further binds to a DNA consensus sequence of target immune, inflammatory or glial marker (e.g., GFAP, AIF1) genes. Similarly, the binding of AGE and other DAMP ligands to RAGE receptor, causes ERK1/2 phosphorylation that further leads to activation and phosphorylation of the NEMO-IKK complex, NF-κB activation, and subsequent translocation of the NF-κB dimer (e.g., p65/p50 or p50/p50 subunit or their putative combination) to the nucleus to regulate transcription of immune and inflammatory genes including glial markers, e.g., GFAP, AIF1. Over-expression of RAGE produces vicious cycles that perpetuate oxidative stress and contribute to neuroinflammation by nuclear factor-kB (NF-kB) up-regulation. Black arrows indicate the activation process and multiple arrows indicate several unknown intermediates in the signaling cascade. AGE, advanced glycation end-products; AIF1, allograft inflammatory factor 1 (also known as IBA1, ionized calcium-binding adapter molecule 1); DAMP, damage-associated molecular patterns; ERK1/2, extracellular signal-regulated kinase 1 and 2; GFAP, glial fibrillary acidic protein; IKKα, inhibitor of nuclear factor kappa-B kinase subunit alpha (IKKA; also known as CHUK, component of inhibitor of nuclear factor kappa B kinase complex); IKKβ, inhibitor of nuclear factor kappa-B kinase subunit beta (IKKB; also known as IKBKB); IL1A, interleukin 1 alpha; IL1B, interleukin 1 beta; IL1R, interleukin 1 receptor; IRAK, interleukin 1 receptor associated kinase 1; IRAK, interleukin 1 receptor-associated kinase; IκB, inhibitor of nuclear factor kappa B; LPS, lipopolysaccharide; MYD88, MYD88 innate immune signal transduction adaptor (also known as myeloid differentiation primary response gene 88; NEMO, NF-kappaB essential modulator (also known as IKBKG, inhibitor of nuclear factor kappa-B kinase regulatory subunit gamma); NF-κB, nuclear factor kappa B; P, phosphate group; p50, protein p50 (the functional subunit of the 105 kD precursor protein coded by the gene NFKB1, nuclear factor kappa B subunit 1); p52, protein p52 (the functional subunit of the 100 kD precursor protein coded by the gene NFKB2, nuclear factor kappa B subunit 2); p65, protein p65 (also known as RELA, RELA proto-oncogene, NF-KB Subunit or V-Rel avian reticuloendotheliosis viral oncogene homolog A); PAMPs, pathogen-associated molecular patterns; RAGE, receptor for advanced glycation end-products; TAK1, transforming growth factor beta activated kinase 1; TLR, toll-like receptor; TNFA, tumor necrosis factor alpha; TNFR, tumor necrosis factor receptor; TRAF, tumor necrosis actor receptor-associated factor.

Figure 7

JAK-STAT signaling in neuroinflammatory response. Schematic representation depicting activation and regulation of JAK/STAT signaling pathways by various inflammatory ligands. The JAK family has four main members: JAK1, JAK2, JAK3, and TYK2. Black arrows indicate the activation process. Inflammatory mediators and growth factors bind to their corresponding receptors leading to receptor dimerization and recruitment of related JAKs. These mediators include, but are not limited to, interferons, such as interferon alpha, interferon beta, and interferon gamma; interleukin 2, interleukin 3, interleukin 4, interleukin 5, interleukin 6, interleukin 7, interleukin 9, interleukin 11, interleukin 15, interleukin 21; colony stimulating factor 2, colony stimulating factor 3; oncostatin M; leukemia inhibitory factor; and ciliary neurotrophic factor. JAK activation leads to tyrosine phosphorylation of the receptors and the formation of docking sites for various STATs. The activated JAKs phosphorylate (P) and activate STATs. Some JAKs are associated with many different cytokine receptors, but JAK3 associates with only IL2, predominantly to its gamma chain subunit. The STAT family consists of six members: STAT1, STAT2, STAT3, STAT4, STAT5 and STAT6, which upon phosphorylation dissociate from the receptor to form homodimers or heterodimers and translocate to the nucleus and bind to transcription factor binding sites on the target DNA to regulate transcription of immune and inflammatory genes including glial markers, e.g., GFAP, AIF1. AIF1, allograft inflammatory factor 1 (also known as IBA1, ionized calcium-binding adapter molecule 1); CNTF, ciliary neurotrophic factor; CSF2, colony stimulating factor 2; CSF3, colony stimulating factor 3; GFAP, glial fibrillary acidic protein; gp130, glycoprotein 130; IFNA, interferon alpha; IFNB, interferon beta; IFNG, interferon gamma; IFNR, interferon receptor; IL11, interleukin 11; IL15, interleukin 15; IL2, interleukin 2; IL21, interleukin 21; IL2R, interleukin 2 receptor; IL3, interleukin 3; IL3R/βC, interleukin 3 receptor beta chain subunit; IL4, interleukin 4; IL5, interleukin 5; IL6, interleukin 6; IL6R, interleukin 6 receptor; IL7, interleukin 7; IL9, interleukin 9; JAK1, janus kinase 1; JAK2, janus kinase 2; JAK3, janus kinase 3; JAK-STAT, janus kinase-signal transducer and activator of transcription; LIF, leukemia inhibitory factor; OSM, oncostatin M; P, phosphate group; STAT1, signal transducer and activator of transcription 1; STAT2, signal transducer and activator of transcription 2; STAT3, signal transducer and activator of transcription 3; STAT4, signal transducer and activator of transcription 4; STAT5, signal transducer and activator of transcription 5; STAT6, signal transducer and activator of transcription 6; TYK2, tyrosine kinase 2.

Figure 8

MAPK/ERK/JNK signaling in neuroinflammatory response. Schematic representation depicts MAP kinase activation by growth factors, stressor and cytokines which triggers a phosphorylation cascade. Agonist binding to TGFBR, IL1R, TNFR, stress receptors or CXCR2 leads to activation of the MAP3K, which has potential to activate various other MAP kinases by phosphorylating and activating the respective MAP2K. MAP2K has a restricted specificity for MAP kinase substrates. Upon activation, JNK, ERK1/2, and p38 further regulate gene transcription through activation and recruitment of transcription factors such as ATF2, CREB, NFkB, AP1 and AP2ε to the nucleus to regulate transcription of immune and inflammatory genes including glial markers, e.g., GFAP and AIF1. Arrows indicate the activation process in the signaling cascade and multiple arrows indicate several intermediates in the signaling cascade. AIF1, allograft inflammatory factor 1 (also known as IBA1, ionized calcium-binding adapter molecule 1); AP1, activator protein 1 (also known as JUN, Jun protooncogene AP1 transcription factor subunit or V-Jun avian sarcoma virus 17 oncogene homolog); AP2ε, transcription factor AP 2 epsilon (also known as TFAP2E); ATF2, activating transcription factor 2; CREB, cyclic AMP response element binding protein; CXCL1, C-X-C motif chemokine ligand 1; CXCR2, C-X-C motif chemokine receptor 2; ERK 1/2, extracellular signal-regulated kinase 1 and 2; GFAP, glial fibrillary acidic protein; IL1A, interleukin 1alpha; IL1B, interleukin 1 beta; IL1R, interleukin 1 receptor; JNK, c-Jun N-terminal kinase; MAP2K, mitogen activated protein kinase kinase; MAP3K, mitogen activated protein kinase kinase kinase; NFkB, nuclear factor kappa-B; P, phosphate group; p38, p38 mitogen activated protein kinase (p38 MAPK); TGFB, transforming growth factor beta; TGFBR, transforming growth factor beta receptor; TNFA, tumor necrosis factor alpha; TNFR, tumor necrosis factor receptor.