ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease

In the paper

“ROS originating from both NOX and the mitochondria may act as second messengers to propagate immune activation”

In the paper

“Furthermore, microglia respond to damage-associated molecular patterns (DAMPs)—molecules released from damaged cells—by the production of ROS, which becomes elevated and sustained in disease [27,28,29].”

What the sources say

• Not checked yetcites [27] Veerhuis, 1996, Amyloid beta protein primes cultured rat microglial cells for an enhanced phorbol 12-myristate 13-acetate-induced respiratory burst activity, J. Neurochem. source
• Not checked yetcites [28] Klegeris, 1997, beta-amyloid protein enhances macrophage production of oxygen free radicals and glutamate, J. Neurosci. Res. source
• Not checked yetcites [29] Schilling, 2011, Amyloid-β-induced reactive oxygen species production and priming are differentially regulated by ion channels in microglia, J. Cell. Physiol. source

In the paper

“In Alzheimer’s disease (AD), the most common form of dementia, microglia surround amyloid plaques and respond to amyloid-β with a pro-inflammatory phenotype characterised by cytokine expression (e.g., interleukins (IL) 1β and 6 and tumour necrosis factor α (TNFα)) that may initially limit amyloidosis but likely becomes overzealous and neurotoxic [12,13,14].”

What the sources say

• Not checked yetcites [12] Mielke, 2011, Reactive glia not only associates with plaques but also parallels tangles in Alzheimer’s disease, Am. J. Pathol. source
• Not checked yetcites [13] Hickman, 2008, Microglial Dysfunction and Defective β-Amyloid Clearance Pathways in Aging Alzheimer’s Disease Mice, J. Neurosci. source
• Not checked yetcites [14] Zhao, 2017, Microglia limit the expansion of β-amyloid plaques in a mouse model of Alzheimer’s disease, Mol. Neurodegener. source

In the paper

“DAM facilitate persistent inflammation and reactive oxygen species (ROS) generation.”

In the paper

“Microglia also phagocytose α-synuclein, the constituent protein of Lewy bodies in Parkinson’s and Lewy Body dementias, and become pro-inflammatory in the process, expressing cytokines (IL1β, IL6, TNFα), reactive oxygen species (ROS) and prostaglandin synthesising cyclooxygenase 2 (COX2) [24,25,26].”

What the sources say

• Not checked yetcites [24] Croisier, 2005, Microglial inflammation in the parkinsonian substantia nigra: Relationship to alpha-synuclein deposition, J. Neuroinflamm. source
• Not checked yetcites [25] Su, 2008, Synuclein activates microglia in a model of Parkinson’s disease, Neurobiol. Aging source
• Not checked yetcites [26] Kim, 2013, Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia, Nat. Commun. source

In the paper

“Since oxidative stress is a hallmark of AD, indicated by lipid peroxidation [30,31,32,33], protein oxidation [34,35] and mitochondrial DNA damage [36]”

What the sources say

• Not checked yetcites [30] Sung, 2004, Lipid peroxidation and oxidative imbalance: Early functional events in Alzheimer’s disease, J. Alzheimers Dis. JAD source
• Not checked yetcites [31] Clark, 2000, Increased 8,12-iso-iPF2α-VI in Alzheimer’s disease: Correlation of a noninvasive index of lipid peroxidation with disease severity, Ann. Neurol. source
• Not checked yetcites [32] Lovell, 1995, Elevated thiobarbituric acid-reactive substances and antioxidant enzyme activity in the brain in Alzheimer’s disease, Neurology source
• Not checked yetcites [33] Subbarao, 1990, Autopsy samples of Alzheimer’s cortex show increased peroxidation in vitro, J. Neurochem. source
• Not checked yetcites [34] Hensley, 1995, Brain regional correspondence between Alzheimer’s disease histopathology and biomarkers of protein oxidation, J. Neurochem. source
• Not checked yetcites [35] Smith, 1991, Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease, Proc. Natl. Acad. Sci. USA source
• Not checked yetcites [36] Mecocci, 1994, Oxidative damage to mitochondrial DNA is increased in Alzheimer’s disease, Ann. Neurol. source

In the paper

“it is hypothesised that elevated and dysregulated ROS production from DAM contributes to oxidative stress, leading to neuronal death.”

In the paper

“Neuroinflammation and oxidative stress (OS) are undoubtedly hallmarks of neurodegeneration, contributing to disease progression.”

What the sources say

• Not checked yetcites [42] Heneka, 2015, Neuroinflammation in Alzheimer’s disease, Lancet Neurol. source
• Not checked yetcites [43] Trushina, 2017, Oxidative Stress, Synaptic Dysfunction, and Alzheimer’s Disease, J. Alzheimers Dis. JAD source
• Not checked yetcites [44] Reiss, 2018, Amyloid toxicity in Alzheimer’s disease, Rev. Neurosci. source

In the paper

“Nevertheless, data suggest NOX2, along with mediating sustained ROS production, is a driver of excessive inflammation in response to neuronal injury and may impede inflammatory resolution in vivo.”

In the paper

“NOX activation is evident in the AD brain. The NOX2 regulatory subunits, p47phox and p67phox, are translocated from the cytosolic to the membranous fractions of AD brains, suggesting NOX2 activation [113].”

What the sources say

• Not checked yetcites [113] Shimohama, 2000, Activation of NADPH oxidase in Alzheimer’s disease brains, Biochem. Biophys. Res. Commun. source

In the paper

“NOX4 is expressed in the mammalian brain, however specific proteomic expression in microglia is unknown.”

In the paper

“NOX1 transcript and protein expression have been described in microglia isolated from Cx3cr1-enhanced green fluorescent protein (EGFP) reporter mice [77], although expression has not been demonstrated in the mouse brain elsewhere, to our knowledge [65].”

What the sources say

• Not checked yetcites [77] Gervais, 2008, Neurotoxic Activation of Microglia Is Promoted by a Nox1-Dependent NADPH Oxidase, J. Neurosci. source
• Not checked yetcites [65] Sorce, 2009, NOX Enzymes in the Central Nervous System: From Signaling to Disease, Antioxid. Redox Signal. source

In the paper

“Unlike mitochondrial ROS, which are by-products of oxidative phosphorylation, ROS generated from NOX are deliberate and part of the antimicrobial armoury of phagocytes [58].”

What the sources say

• Not checked yetcites [58] Darrah, 2000, Cooperation between reactive oxygen and nitrogen intermediates in killing of Rhodococcus equi by activated macrophages, Infect. Immun. source

In the paper

“Indeed, the expression of cytosolic regulatory subunits of NOX2 (p67phox, p47phox and p40phox) is positively correlated with disease progression and oxidative stress in AD, whilst expression of membrane-bound flavocytochrome b558 subunits (gp91phox and p22phox) is stable [68].”

What the sources say

• Not checked yetcites [68] Ansari, 2011, NADPH-oxidase activation and cognition in Alzheimer disease progression, Free Radic. Biol. Med. source

In the paper

“Hence, DAMP signalling on these receptors may underpin excessive ROS production by inflammatory-related phagocytic activation and prime a vicious cycle of DAMP-induced neuronal damage by oxidative stress [86,96] (Figure 2).”

What the sources say

• Not checked yetcites [86] Hou, 2018, Complement receptor 3 mediates NADPH oxidase activation and dopaminergic neurodegeneration through a Src-Erk-dependent pathway, Redox Biol. source
• Not checked yetcites [96] Bell, 2013, Toll-like receptor 4-dependent microglial activation mediates spinal cord ischemia-reperfusion injury, Circulation source

In the paper

“Upon activation by the assembly of multiple subunits, NOX enzymes generate the superoxide radical (O2•–). The exception is NOX4, which is constitutively active, independent of co-expression with regulatory subunits, and mostly produces H2O2 [56,57].”

What the sources say

• Not checked yetcites [56] Geiszt, 2000, Identification of renox, an NAD(P)H oxidase in kidney, Proc. Natl. Acad. Sci. USA source
• Not checked yetcites [57] Shiose, 2001, A novel superoxide-producing NAD(P)H oxidase in kidney, J. Biol. Chem. source

In the paper

“Knockdown of NOX4 in these cells suppresses both ROS and interleukin (IL)6 production, confirming a link between NOX4 activation and pro-inflammatory cytokine expression.”

What the sources say

• Not checked yetcites [76] Li, 2009, NOX4 expression in human microglia leads to constitutive generation of reactive oxygen species and to constitutive IL-6 expression, J. Innate Immun. source

In the paper

“NOX2 is expressed robustly in both human and murine microglia and the adult CNS and throughout development, indicating a strong evolutionary requirement for its expression in the CNS.”

In the paper

“Loss-of-function mutations in NOX2 result in chronic granulomatous disease, a rare syndrome described in 1957 and characterised by recurrent infections caused by impaired phagocytosis [46,47,48].”

What the sources say

• Not checked yetcites [46] Berendes, 1957, A fatal granulomatosus of childhood: The clinical study of a new syndrome, Minn. Med.
• Not checked yetcites [47] Quie, 1967, In vitro bactericidal capacity of human polymorphonuclear leukocytes: Diminished activity in chronic granulomatous disease of childhood, J. Clin. Investig. source
• Not checked yetcites [48] Baehner, 1967, Leukocyte oxidase: Defective activity in chronic granulomatous disease, Science source

In the paper

“Interestingly, however, this particular cell line does not express NOX2; this calls into question the validity of the model since NOX2 is the most highly expressed isotype in both human and murine microglia [72,73].”

What the sources say

• Not checked yetcites [72] Zhang, 2014, An RNA-Sequencing Transcriptome and Splicing Database of Glia, Neurons, and Vascular Cells of the Cerebral Cortex, J. Neurosci. source
• Not checked yetcites [73] Zhang, 2016, Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse, Neuron source

In the paper

“CR3, which is upregulated in human AD-associated microglia, contributes to persistent inflammation, NOX2 activation and O2•- release in response to DAMPs, such as amyloid-β [85,98,99,100].”

What the sources say

• Not checked yetcites [85] Fu, 2012, Complement component C3 and complement receptor type 3 contribute to the phagocytosis and clearance of fibrillar Aβ by microglia, Glia source
• Not checked yetcites [98] Zhang, 2011, Microglial MAC1 receptor and PI3K are essential in mediating β-amyloid peptide-induced microglial activation and subsequent neurotoxicity, J. Neuroinflamm. source
• Not checked yetcites [99] Hu, 2008, Macrophage antigen complex-1 mediates reactive microgliosis and progressive dopaminergic neurodegeneration in the MPTP model of Parkinson’s disease, J. Immunol. source
• Not checked yetcites [100] Akiyama, 1990, Brain microglia constitutively express beta-2 integrins, J. Neuroimmunol. source

In the paper

“Pharmacological blockade or microglial-specific knockout of TLR4 or CR3 severely attenuates ROS production by NOX2, indicating NOX2 activation is of microglial origin, despite reported expression of NOX2 in neurons [64,102,103].”

What the sources say

• Not checked yetcites [64] Cooney, 2013, Cellular and temporal expression of NADPH oxidase (NOX) isotypes after brain injury, J. Neuroinflamm. source
• Not checked yetcites [102] Levesque, 2013, The role of MAC1 in diesel exhaust particle-induced microglial activation and loss of dopaminergic neuron function, J. Neurochem. source
• Not checked yetcites [103] Pei, 2007, MAC1 mediates LPS-induced production of superoxide by microglia: The role of pattern recognition receptors in dopaminergic neurotoxicity, Glia source

In the paper

“The rate-limiting step of NOX2 activation is hypothesised to be serine-threonine phosphorylation of p47phox by p21 (cdc42/Rac1)-activated kinase-1 [62].”

What the sources say

• Not checked yetcites [62] Roepstorff, 2008, Stimulus-dependent Regulation of the Phagocyte NADPH Oxidase by a VAV1, Rac1, and PAK1 Signaling Axis, J. Biol. Chem. source

In the paper

“Nonetheless, NOX is activated in in vivo models of AD and offsetting this upregulation may limit neurodegeneration and cognitive impairment.”

In the paper

“Evidence from mammalian studies indicates that NOX activation in response to amyloid-β contributes to neurodegeneration and is associated with cerebrovascular pathology.”

In the paper

“Furthermore, age-related amyloid deposition, microgliosis and ROS production were dependent on NOX2 expression and findings correlated with post-mortem tissue from young and aged human samples [125].”

What the sources say

• Not checked yetcites [125] Geng, L., Fan, L.M., Liu, F., Smith, C., and Li, J.-M. (2020). Nox2 dependent redox-regulation of microglial response to amyloid-β stimulation and microgliosis in aging. Sci. Rep., 10. source

In the paper

“Further, microglia in AD brains strongly express gp91phox, implying NOX2 activation is localised to microglia in AD [119].”

What the sources say

• Not checked yetcites [119] Gupta, 2010, NOX activity is increased in mild cognitive impairment, Antioxid. Redox Signal. source

In the paper

“Indeed, Aβ-42 induces NOX2 expression in microglia and this response is accentuated in aged mice [125].”

What the sources say

• Not checked yetcites [125] Geng, L., Fan, L.M., Liu, F., Smith, C., and Li, J.-M. (2020). Nox2 dependent redox-regulation of microglial response to amyloid-β stimulation and microgliosis in aging. Sci. Rep., 10. source

In the paper

“For example, microglial activation by the TLR4 agonist, LPS, results in degradation of IκB, translocation of NFκB to the nucleus and activation of κB-containing DNA response elements, including TNFα, IL1β and cyclooxygenase-2 (COX2).”

What the sources say

• Not checked yetcites [140] Dresselhaus, E.C., and Meffert, M.K. (2019). Cellular Specificity of NF-κB Function in the Nervous System. Front. Immunol., 10. source

In the paper

“whilst neurovascular changes were not reported, increased NOX activity and NOX4 expression were age-dependent and NOX activity was, again, strongly correlated with cognitive impairment [117].”

What the sources say

• Not checked yetcites [117] Gupta, 2011, Cognitive impairment in humanized APP×PS1 mice is linked to Aβ(1-42) and NOX activation, Neurobiol. Dis. source

In the paper

“Furthermore, amyloid-β stimulates NOX2 in rat microglia and peripheral phagocytes, whilst phagocytes isolated from patients with chronic granulomatosis disease (caused by a genetic deficiency of NOX2) do not respond to stimulation with amyloid-β [121].”

What the sources say

• Not checked yetcites [121] Bianca, 1999, β-Amyloid Activates the O⨪2 Forming NADPH Oxidase in Microglia, Monocytes, and Neutrophils A POSSIBLE INFLAMMATORY MECHANISM OF NEURONAL DAMAGE IN ALZHEIMER’S DISEASE, J. Biol. Chem. source

In the paper

“Also, NOX1 and 3 expression is increased in early AD, followed by upregulation of markers of mitochondrial dysfunction [114].”

What the sources say

• Not checked yetcites [114] Wands, 2006, Molecular indices of oxidative stress and mitochondrial dysfunction occur early and often progress with severity of Alzheimer’s disease, J. Alzheimers Dis. JAD source

In the paper

“In LPS-stimulated macrophages, the peripheral cousins of microglia, the antioxidant lutein scavenges intracellular O2•– and H2O2 and reduces NFκB activation, whilst TLR4 signalling and MAPK activation remained [146].”

What the sources say

• Not checked yetcites [146] Kim, 2008, The non-provitamin A carotenoid, lutein, inhibits NF-κB-dependent gene expression through redox-based regulation of the phosphatidylinositol 3-kinase/PTEN/Akt and NF-κB-inducing kinase pathways: Role of H2O2 in NF-κB activation, Free Radic. Biol. Med. source

In the paper

“NFκB activation by TLR4 signalling results in neuroinflammation and cognitive impairment [141,142].”

What the sources say

• Not checked yetcites [141] Wang, 2012, The transcriptional specificity of NF-κB dimers is coded within the κB DNA response elements, Cell Rep. source
• Not checked yetcites [142] Zhao, 2019, Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice, Sci. Rep. source

In the paper

“Knockdown of gp91phox or application of N-acetyl cysteine (the antioxidant, NAC) in infected macrophages reduced NFκB activation levels.”

What the sources say

• Not checked yetcites [147] Li, H., Luo, Y.-F., Wang, Y.-S., Yang, Q., Xiao, Y.-L., Cai, H.-R., and Xie, C.-M. (2020, June 16). Using ROS as a Second Messenger, NADPH Oxidase 2 Mediates Macrophage Senescence via Interaction with NF-κB during Pseudomonas aeruginosa Infection. Available online: https://www.hindawi.com/journals/omcl/2018/9741838/. source

In the paper

“However, p47phox and p67phox are not expressed in neurons or astrocytes isolated from rats, but cytosolic translocation of both subunits does occur in microglia [113].”

What the sources say

• Not checked yetcites [113] Shimohama, 2000, Activation of NADPH oxidase in Alzheimer’s disease brains, Biochem. Biophys. Res. Commun. source

In the paper

“Microglial NFκB is a dimer of p50 (NFκB1) and p65 (Rel-A) [138,139] and is sequestered in the cytoplasm by inhibitor of κB (IκB).”

What the sources say

• Not checked yetcites [138] Wang, W.-Y., Tan, M.-S., Yu, J.-T., and Tan, L. (2015). Role of pro-inflammatory cytokines released from microglia in Alzheimer’s disease. Ann. Transl. Med., 3.
• Not checked yetcites [139] Zheng, 2011, Structural studies of NF-κB signaling, Cell Res. source

In the paper

“Interestingly, GRN−/− mice display high numbers of LDAM which are ROS-generating and pro-inflammatory, yet defective in phagocytosis [162].”

What the sources say

• Not checked yetcites [162] Marschallinger, 2020, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain, Nat. Neurosci. source

In the paper

“The family includes extracellular signal-regulated kinases (ERK1/2), c-Jun N-terminal kinase (JNK) and p38 MAPKs.”

In the paper

“This identifies endogenous ROS derived from mitochondria as critical mediators of the neuroimmune response to LPS, as well as exogenous ROS, i.e., from neuronal damage.”

What the sources say

• Not checked yetcites [158] Park, 2015, Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-κB pathways, Neurosci. Lett. source

In the paper

“For example, IL1 signalling results in activation of the small G-protein, Ras, which in turn activates MKK6, resulting in activation of p38 MAPK [153].”

What the sources say

• Not checked yetcites [153] McDermott, 2002, Ras Participates in the Activation of p38 MAPK by Interleukin-1 by Associating with IRAK, IRAK2, TRAF6, and TAK-1, J. Biol. Chem. source

In the paper

“Moreover, BV-2 microglia treated with advanced oxidation protein products, a hallmark of oxidative stress, displayed increased NOX4 expression and elevated ROS, along with p38 MAPK and JNK activation [155].”

What the sources say

• Not checked yetcites [155] Liu, 2020, Advanced oxidation protein products induce microglia-mediated neuroinflammation via MAPKs-NF-κB signaling pathway and pyroptosis after secondary spinal cord injury, J. Neuroinflamm. source

In the paper

“This evidence shows that lipid droplets are an important element of the redox response in microglia and these organelles are associated with AD-risk genes and neuronal death.”

What the sources say

• Not checked yetcites [162] Marschallinger, 2020, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain, Nat. Neurosci. source
• Not checked yetcites [163] Liu, 2015, Glial Lipid Droplets and ROS Induced by Mitochondrial Defects Promote Neurodegeneration, Cell source
• Not checked yetcites [164] Liu, 2017, The Glia-Neuron Lactate Shuttle and Elevated ROS Promote Lipid Synthesis in Neurons and Lipid Droplet Accumulation in Glia via APOE/D, Cell Metab. source

In the paper

“Specific pharmacological suppression of mROS by mitoTEMPO in LPS-stimulated primary murine microglia resulted in reduced activation of all three MAPKs and limited NFκB nuclear translocation, along with the reduced expression of a battery of pro-inflammatory factors (TNFα, IL1β, IL6, iNOS and Cox-2) [158].”

What the sources say

• Not checked yetcites [158] Park, 2015, Mitochondrial ROS govern the LPS-induced pro-inflammatory response in microglia cells by regulating MAPK and NF-κB pathways, Neurosci. Lett. source

In the paper

“Ethanol-related neurodegeneration is associated with increased microglial NFκB activation and gp91phox expression [150].”

What the sources say

• Not checked yetcites [150] Qin, 2012, NADPH oxidase and reactive oxygen species contribute to alcohol-induced microglial activation and neurodegeneration, J. Neuroinflamm. source

In the paper

“The mitogen-activated protein kinase (MAPK) family comprises three subgroups of serine/threonine kinases activated in response to a range of cellular signals, including proinflammatory cytokines, environmental stress and growth factors.”

In the paper

“Lipid droplets (LD) are organelles formed in the endoplasmic reticulum, comprising of a neutral lipid (triacylglycerol and cholesteryl ester) core encapsulated by a phospholipid monolayer, thought to function as a store of energy [160].”

What the sources say

• Not checked yetcites [160] Jackson, 2019, Lipid droplet biogenesis, Curr. Opin. Cell Biol. source

In the paper

“Critically, these findings were correlated with human post-mortem brain samples from alcoholic patients, yet the effect of NOX inhibition on NFκB activation in humans was not noted [150].”

What the sources say

• Not checked yetcites [150] Qin, 2012, NADPH oxidase and reactive oxygen species contribute to alcohol-induced microglial activation and neurodegeneration, J. Neuroinflamm. source

In the paper

“Antioxidant treatment or human superoxide dismutase 1 (SOD1) expression in flies reduces LD formation and attenuates neurodegeneration [163].”

What the sources say

• Not checked yetcites [163] Liu, 2015, Glial Lipid Droplets and ROS Induced by Mitochondrial Defects Promote Neurodegeneration, Cell source

In the paper

“MAPKs themselves exert their effects on cellular physiology via myriad effectors, including transcription factors and further kinases [152].”

What the sources say

• Not checked yetcites [152] Kaminska, 2009, MAPK signal transduction underlying brain inflammation and gliosis as therapeutic target, Anat. Rec. source

In the paper

“MAPKs share a common chain of activation mediated by sequential, three-tiered phosphorylation of upstream kinases, i.e., signal transduction is mediated by phosphorylation of a MAPK kinase kinase (MKKK), which in turn activates a MAPK kinase (MKK) which activates the MAPK.”

What the sources say

• Not checked yetcites [152] Kaminska, 2009, MAPK signal transduction underlying brain inflammation and gliosis as therapeutic target, Anat. Rec. source

In the paper

“This was mediated by both a reduction in heme availability and biliverdin and carbon monoxide, by-products of heme metabolism by HO-1 which may facilitate attenuation of TLR4 signalling by NOX inhibition [173,174].”

What the sources say

• Not checked yetcites [173] Nakahira, 2006, Carbon monoxide differentially inhibits TLR signaling pathways by regulating ROS-induced trafficking of TLRs to lipid rafts, J. Exp. Med. source
• Not checked yetcites [174] Lanone, 2004, Induction of heme oxygenase-1 inhibits NAD(P)H oxidase activity by down-regulating cytochrome b558 expression via the reduction of heme availability, J. Biol. Chem. source

In the paper

“Furthermore, NCOA7 is induced in epithelial cells in response to rhinovirus infection and LPS-stimulated macrophages, the peripheral myeloid cousins of microglia [186,187].”

What the sources say

• Not checked yetcites [186] Baines, 2013, Novel immune genes associated with excessive inflammatory and antiviral responses to rhinovirus in COPD, Respir. Res. source
• Not checked yetcites [187] Alasoo, 2015, Transcriptional profiling of macrophages derived from monocytes and iPS cells identifies a conserved response to LPS and novel alternative transcription, Sci. Rep. source

In the paper

“Loss of OXR1 results in pronounced microgliosis whilst neuronal OXR1 overexpression delays inflammation, indicating OXR1 regulation of microglial activation in a non-cell-autonomous fashion [184].”

What the sources say

• Not checked yetcites [184] Liu, 2015, Neuron-specific antioxidant OXR1 extends survival of a mouse model of amyotrophic lateral sclerosis, Brain source

In the paper

“Expression of these proteins by Nrf2 in microglia may represent a pathway that can be modulated to enhance innate defences and combat oxidative stress.”

In the paper

“The function of these redox regulators in microglia is unclear as of yet, however, many of these proteins are linked to inflammation, suggesting functionality in microglia.”

In the paper

“Many antioxidant proteins are understood to function in the CNS, including classical antioxidants (superoxide dismutase, glutathione reductase, catalase, etc. reviewed in [38]) and more recently TBC, LysM, domain catalytic (TLDc) proteins (oxidation resistance 1, nuclear receptor coactivator 7, Tbc1d24, etc. reviewed in [166]).”

What the sources say

• Not checked yetcites [38] Salim, 2017, Oxidative Stress and the Central Nervous System, J. Pharmacol. Exp. Ther. source
• Not checked yetcites [166] Finelli, 2017, TLDc proteins: New players in the oxidative stress response and neurological disease, Mamm. Genome source

In the paper

“The two are undoubtedly linked; however, it is not clear how ROS interact with glia to elicit an immune response, although this may involve reciprocal regulation between NOX2 and NFκB [147].”

What the sources say

• Not checked yetcites [147] Li, H., Luo, Y.-F., Wang, Y.-S., Yang, Q., Xiao, Y.-L., Cai, H.-R., and Xie, C.-M. (2020, June 16). Using ROS as a Second Messenger, NADPH Oxidase 2 Mediates Macrophage Senescence via Interaction with NF-κB during Pseudomonas aeruginosa Infection. Available online: https://www.hindawi.com/journals/omcl/2018/9741838/. source

In the paper

“Intracranial injection of the isothiocyanate, sulforaphane, enhanced Nrf2 levels which limited expression of pro-inflammatory microglial markers and conferred neuroprotection [168,169,170].”

What the sources say

• Not checked yetcites [168] Innamorato, 2008, The transcription factor Nrf2 is a therapeutic target against brain inflammation, J. Immunol. Baltim. source
• Not checked yetcites [169] Rojo, 2010, Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson’s disease, Glia source
• Not checked yetcites [170] Jazwa, 2011, Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism, Antioxid. Redox Signal. source

In the paper

“Finally, LDAM are important regulators of oxidative stress and a mechanism by which protective inflammation may become dysregulated and damaging in ageing and neurodegeneration.”

In the paper

“This signature involved the downregulation of microglial homeostatic genes (Tmem119, Cx3cr1) and overexpression of ROS-related genes Cybb (p91phox), Cyba (p22phox) and Nos2 (nitric oxide synthase 2); and pro-inflammatory genes Il1b, Cd47 and Prkcd (protein kinase C-δ).”

What the sources say

• Not checked yetcites [181] Mendiola, 2020, Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation, Nat. Immunol. source

In the paper

“The mechanism of LD accumulation in response to elevated ROS in flies and the perturbation of this mechanism by ApoeE-ε4 indicates LDAM are protective, potentially by sequestering peroxidised lipids [163,164].”

What the sources say

• Not checked yetcites [163] Liu, 2015, Glial Lipid Droplets and ROS Induced by Mitochondrial Defects Promote Neurodegeneration, Cell source
• Not checked yetcites [164] Liu, 2017, The Glia-Neuron Lactate Shuttle and Elevated ROS Promote Lipid Synthesis in Neurons and Lipid Droplet Accumulation in Glia via APOE/D, Cell Metab. source

In the paper

“The function of these redox regulators in microglia is unclear as of yet, however, many of these proteins are linked to inflammation, suggesting functionality in microglia.”

In the paper

“However, it is feasible that ROS act as secondary messengers in microglia to propagate inflammatory states and may contribute to immune dysregulation, leading to persistent and inappropriate inflammation.”

In the paper

“This implies LDAM are dysfunctional in neurodegeneration, where they may be unable to clear aggregated protein but would induce oxidative stress and inflammatory cascades.”

What the sources say

• Not checked yetcites [162] Marschallinger, 2020, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain, Nat. Neurosci. source

In the paper

“Molecular pathways in microglia contributing to neurodegeneration undoubtedly involve inflammatory-mediated ROS production by activation of NOX.”

In the paper

“In microglia, Nrf2-deficiency promotes inflammatory marker expression (IL6, Cox2, iNOS) whilst inhibiting anti-inflammatory marker expression (arginase 1, IL4) in response to LPS and MPTP [168,169].”

What the sources say

• Not checked yetcites [168] Innamorato, 2008, The transcription factor Nrf2 is a therapeutic target against brain inflammation, J. Immunol. Baltim. source
• Not checked yetcites [169] Rojo, 2010, Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson’s disease, Glia source

In the paper

“The mechanism by which TLDc proteins confer stress resistance is unclear, however, specific disruption of the OXR1 TLDc domain in mice is sufficient to cause neurodegeneration and loss-of-function polymorphisms in human TLDc proteins result in a neurodegenerative phenotype [182,183].”

What the sources say

• Not checked yetcites [182] Finelli, 2016, The Evolutionarily Conserved Tre2/Bub2/Cdc16 (TBC), Lysin Motif (LysM), Domain Catalytic (TLDc) Domain Is Neuroprotective against Oxidative Stress, J. Biol. Chem. source
• Not checked yetcites [183] Wang, 2019, Loss of Oxidation Resistance 1, OXR1, Is Associated with an Autosomal-Recessive Neurological Disease with Cerebellar Atrophy and Lysosomal Dysfunction, Am. J. Hum. Genet. source

In the paper

“Finally, a unique, short-isoform of NCOA7, NCOA7-B or NCOA7-AS, is strongly linked to inflammatory activation, especially by viral-related stimuli such as interferons (IFNs), and functional inhibition of endosome-mediated viral-entry by NCOA7-B has been demonstrated [185].”

What the sources say

• Not checked yetcites [185] Doyle, 2018, The interferon-inducible isoform of NCOA7 inhibits endosome-mediated viral entry, Nat. Microbiol. source

In the paper

“It is unlikely ROS are the primary trigger of inflammation in Alzheimer’s disease; this is likely mediated by DAMPs associated with toxic protein aggregation.”

In the paper

“However, LDAM are also ROS-generating and pro-inflammatory yet defective in phagocytosis in murine models [162].”

What the sources say

• Not checked yetcites [162] Marschallinger, 2020, Lipid-droplet-accumulating microglia represent a dysfunctional and proinflammatory state in the aging brain, Nat. Neurosci. source

In the paper

“Microgliosis and sulforaphane neuroprotection were attenuated in Nrf2-deficient mice which confirms a mechanistic link between Nrf2 and immune regulation.”

What the sources say

• Not checked yetcites [168] Innamorato, 2008, The transcription factor Nrf2 is a therapeutic target against brain inflammation, J. Immunol. Baltim. source
• Not checked yetcites [169] Rojo, 2010, Nrf2 regulates microglial dynamics and neuroinflammation in experimental Parkinson’s disease, Glia source
• Not checked yetcites [170] Jazwa, 2011, Pharmacological targeting of the transcription factor Nrf2 at the basal ganglia provides disease modifying therapy for experimental parkinsonism, Antioxid. Redox Signal. source

In the paper

“Furthermore, the expression of this short-isoform in ovarian follicles is regulated intracellularly by MAPKs, p38 and ERK, which are recognised mediators of the pro-inflammatory response in microglia [191].”

What the sources say

• Not checked yetcites [191] Shkolnik, 2008, Molecular characterization and bioinformatics analysis of Ncoa7B, a novel ovulation-associated and reproduction system-specific Ncoa7 isoform, Reproduction source

In the paper

“For example, the concerted kinase activity of MAPKs and PKC may create a strong pro-oxidant signal by vigorous and persistent phosphorylation of both each other’s activation pathways and NOX2 regulatory subunits, resulting in enhanced and sustained ROS production.”

In the paper

“Notably, many experiments examining the role have been conducted in immortalised microglia, e.g., BV2 cells.”

In the paper

“This likely involves a vicious cycle in which neuroinflammatory signals induce ROS release, which then promotes further deleterious inflammation.”

In the paper

“Gene network analysis identified upregulation of glutathione transferase activity in ROS-generating microglia, which was rescued by acivin, a compound which inhibits glutathione degradation [181].”

What the sources say

• Not checked yetcites [181] Mendiola, 2020, Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation, Nat. Immunol. source

In the paper

“The authors were able to characterise the molecular mechanism of acivin, as well as demonstrate improved functional outcome’s in a mammalian model of neurodegeneration.”

What the sources say

• Not checked yetcites [181] Mendiola, 2020, Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation, Nat. Immunol. source

In the paper

“Acivin effectively reduced oxidative stress and neuronal death in the EAE model without toxicity to other CNS cell types.”

What the sources say

• Not checked yetcites [181] Mendiola, 2020, Transcriptional profiling and therapeutic targeting of oxidative stress in neuroinflammation, Nat. Immunol. source