Novel Molecular Insights into Classical and Alternative Activation States of Microglia as Revealed by Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC)-based Proteomics*

Bell-Temin, Harris; Culver-Cochran, Ashley E.; Chaput, Dale; Carlson, Christina M.; Kuehl, Melanie N.; Burkhardt, Brant R.; Bickford, Paula C.; Liu, Bin; Stevens, Stanley M.

doi:10.1074/mcp.m115.053926

Cited by 52 publications

(55 citation statements)

References 44 publications

(64 reference statements)

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“…Alveolar MØs are the main source of cathepsins in bleomycin-induced fibrotic lung tissue [43]. Additional genes associated with development and maintenance of alternative MØ activation include TGFBI [44], NEU1 [45], PRCP [46], and DAB2 [47]. Genes that are specifically associated with alternative activation of lung MØs include PLP2 [48] and IFITM1 [49] (Fig.…”

Section: Resultsmentioning

confidence: 99%

A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis

et al. 2017

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BackgroundSystemic sclerosis (SSc) is a multi-organ autoimmune disease characterized by skin fibrosis. Internal organ involvement is heterogeneous. It is unknown whether disease mechanisms are common across all involved affected tissues or if each manifestation has a distinct underlying pathology.MethodsWe used consensus clustering to compare gene expression profiles of biopsies from four SSc-affected tissues (skin, lung, esophagus, and peripheral blood) from patients with SSc, and the related conditions pulmonary fibrosis (PF) and pulmonary arterial hypertension, and derived a consensus disease-associate signature across all tissues. We used this signature to query tissue-specific functional genomic networks. We performed novel network analyses to contrast the skin and lung microenvironments and to assess the functional role of the inflammatory and fibrotic genes in each organ. Lastly, we tested the expression of macrophage activation state-associated gene sets for enrichment in skin and lung using a Wilcoxon rank sum test.ResultsWe identified a common pathogenic gene expression signature—an immune–fibrotic axis—indicative of pro-fibrotic macrophages (MØs) in multiple tissues (skin, lung, esophagus, and peripheral blood mononuclear cells) affected by SSc. While the co-expression of these genes is common to all tissues, the functional consequences of this upregulation differ by organ. We used this disease-associated signature to query tissue-specific functional genomic networks to identify common and tissue-specific pathologies of SSc and related conditions. In contrast to skin, in the lung-specific functional network we identify a distinct lung-resident MØ signature associated with lipid stimulation and alternative activation. In keeping with our network results, we find distinct MØ alternative activation transcriptional programs in SSc-associated PF lung and in the skin of patients with an “inflammatory” SSc gene expression signature.ConclusionsOur results suggest that the innate immune system is central to SSc disease processes but that subtle distinctions exist between tissues. Our approach provides a framework for examining molecular signatures of disease in fibrosis and autoimmune diseases and for leveraging publicly available data to understand common and tissue-specific disease processes in complex human diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0417-1) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis

et al. 2017

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“…All of these results in vivo and in vitro studies indicated that α-LA exerts neuroprotective effects by inducing the polarization of microglia to the M2 phenotype. Previous studies indicated that microglia show a transient M2 phenotype in the ischemic penumbra and express high levels of anti-inflammatory factors to improve neuron survival and reduce cerebral infarct volume within 24 h after ischemic stroke [28,29]. Then, activated microglia shift to the M1 phenotype and worsen tissue destruction and neurological dysfunction.…”

Section: Cellular Physiology and Biochemistrymentioning

confidence: 99%

The Role of Alpha-Lipoic Acid in the Pathomechanism of Acute Ischemic Stroke

Wang¹,

Lv²,

Sun³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Ischemic stroke results in increased cerebral infarction, neurological deficits and neuroinflammation. The underlying mechanisms involving the anti-inflammatory and neuroprotective properties of α-Lipoic acid (α-LA) remain poorly understood. Herein, we investigated the potential role of α-LA in a middle cerebral artery occlusion (MCAO) rat model and an in vitro lipopolysaccharide (LPS)-induced microglia inflammation model. Methods: In the in vivo study, infarct volume was examined by TTC staining and Garcia score was used to evaluate neurologic recovery. The cytokines were evaluated by enzyme-linked immunosorbent assay, and protein expression of microglia phenotype and NF-κB were measured using western blot. In the in vitro study, the expressions of microglia M1/M2 phenotype were evaluated using qRT-PCR, and immunofluorescence staining was used to assess the nuclear translocation of NF-κB. Results: Both 20 mg/kg and 40 mg/kg of α-LA alleviated infarct size, brain edema, and neurological deficits. Furthermore, α-LA induced the polarization of microglia to the M2 phenotype, modulated the expression of IL-1β, IL-6, TNF-α and IL-10, and attenuated the activation of NF-κB after MCAO. α-LA inhibited the expression of M1 markers, increased activation of the M2 markers, and suppressed the nuclear translocation of NF-κB in LPS-stimulated BV2 microglia. Conclusions: α-LA improved neurological outcome in experimental stroke via modulating microglia M1/M2 polarization. The potential mechanism of α-LA might be mediated by inhibition of NF-κB activation via regulating phosphorylation and nuclear translocation of p65.

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“…In the context of TBI, IL-10 is demonstrably higher intrathecally and has been shown to activate the anti-inlammatory subtype of microglia (phenotypically referred to as M2 microglia) involved in matrix formation and the remodeling of tissue [169][170][171]. In a study examining IL-10 in TBI, Knoblach et al administered intravenous IL-10 at 30 min prior to and 1 h after lateral luid percussion TBI in rats.…”

Section: Anti-inlammatory Il-10 In Tbimentioning

confidence: 99%

“…IL-4 and IL-13 can activate the M2a polarization state of microglia, an anti-inlammatory microglia subtype and may be an avenue for potential therapy post-TBI [169,171]. Clinically, in patients undergoing surgery post-severe TBI, IL-4 expression levels were increased in the irst 24 h post-injury in brain tissue samples, while lower IL-4 levels were present in patients undergoing surgery on days 3-5 post-injury; in the late group, IL-4 levels were also signiicantly lower than IL-1β and IFN-γ levels [145].…”

Section: Anti-inlammatory Il-4 In Tbimentioning

confidence: 99%

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

Dugue¹,

Nath²,

Dugue³

et al. 2017

Mechanisms of Neuroinflammation

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This chapter will introduce the reader to the pathophysiology of two devastating neurologic events, traumatic brain injury (TBI) and acute ischemic stroke (AIS). Here we focus on the role of key pro-inlammatory and anti-inlammatory cytokines. Several experimental interventions have been found to modulate cytokine production and brain injury after AIS or TBI. Here minocycline, biological response modiiers, hormonal therapies, omega-3 faty acids, N-acetylcysteine, and cannabinoids will be discussed. In addition, the role of cytokine-induced inlammasomes in both TBI and AIS will be addressed and followed by discussion of pro-inlammatory cytokines (e.g., TNF-α, IL-1β, IL-18, and IFN-γ). Finally, the main anti-inlammatory cytokines, IL-33, IL-10, IL-6, and IL-4, will be discussed in the context of both TBI and AIS. It should be noted that the role of these cytokines is diverse and the dichotomization of classically pro-versus anti-inlammatory cytokines is being re-examined, as many of these cytokines have been found to play dual roles in TBI and AIS brain injury.Keywords: traumatic brain injury, ischemic stroke, cytokines, interleukins, inlammasome Pathophysiology of traumatic brain injuryTraumatic brain injury (TBI) is a major cause of death and disability worldwide [1,2]. It is one of the most commonly diagnosed neurological disorders in the United States, impacting people of a variety of ages and segments of society [3]. In Europe, the economic cost of © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.TBI is over 33 billion euros per year [4]. Continued surveillance and research is being done to reduce primary and secondary TBI [as well as acute ischemic stroke(AIS)]-induced brain injury [1].The pathophysiology of TBI begins with the initial brain trauma (i.e., the primary injury). This primary injury results from mechanical damage that disrupts the blood-brain barrier (BBB), alters the vasculature and damages brain tissue. The resulting injured glia and neurons release their intracellular contents (i.e., damage-associated molecular paterns; (DAMPs)) into the extracellular space and activate neighboring glia and neurons. Activated glia and neurons then produce molecular signals that can both exacerbate and mend the acute injury and contribute to long-term recovery [5][6][7][8][9]. These downstream molecular and cellular processes (i.e., the secondary injury in TBI) are the focus of many pre-clinical and clinical therapeutic studies. Secondary injury in TBI involves a host of molecular and cellular responses to the The pathophysiology of AIS and TBI share common mechanisms. The initial insult in AIS, an occlusion of blood low resulting in a core infarct zone surrounded by a poorly perfused penumbra, versus the initial primary physical impact in TBI both result in pe...

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Novel Molecular Insights into Classical and Alternative Activation States of Microglia as Revealed by Stable Isotope Labeling by Amino Acids in Cell Culture (SILAC)-based Proteomics*

Cited by 52 publications

References 44 publications

A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis

A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis

The Role of Alpha-Lipoic Acid in the Pathomechanism of Acute Ischemic Stroke

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

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