Isoflurane preconditioning ameliorates electromagnetic pulse-induced neural damage by shifting microglia polarization toward anti-inflammatory phenotype via upregulation of SOCS1

Microglia activation and subsequent pro-inflammatory responses play a key role in the development of neuropathic pain. The process of microglia polarization towards pro-inflammatory phenotype often occurs during neuroinflammation. Recent studies have demonstrated an active role for the gut microbiota in promoting microglial full maturation and inflammatory capabilities via the production of Short-Chain Fatty Acids (SCFAs). However, it remains unclear whether SCFAs is involved in pro-inflammatory/anti-inflammatory phenotypes microglia polarization in the neuropathic pain. In the present study, chronic constriction injury (CCI) was used to induce neuropathic pain in mice, the mechanical withdrawal threshold, thermal hyperalgesia were accomplished. The levels of microglia markers including ionized calcium-binding adaptor molecule 1 (Iba1), cluster of differentiation 11b (CD11b), pro-inflammatory phenotype markers including CD68, interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and anti-inflammatory phenotype markers including CD206, IL-4 in the hippocampus and spinal cord were determined on day 21 after CCI. The results showed that CCI produced mechanical allodynia and thermal hyperalgesia, and also increased the expressions of microglia markers (Iba1, CD11b) and pro-inflammatory phenotype markers (CD68, IL-1β, and TNF-α), but not anti-inflammatory phenotype marker (CD206, IL-4) in the hippocampus and spinal cord, accompanied by increased SCFAs in the gut. Notably, antibiotic administration reversed these abnormalities, and its effects was also bloked by SCFAs administration. In conclusion, data from our study suggest that CCI can lead to mechanical and thermal hyperalgesia, while SCFAs play a key role in the pathogenesis of neuropathic pain by regulating microglial activation and subsequent pro-inflammatory phenotype polarization. Antibiotic administration may be a new treatment for neuropathic pain by reducing the production of SCFAs and further inhibiting the process of microglia polarization.

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Aging, Melatonin, and the Pro- and Anti-Inflammatory Networks

International Journal of Molecular Sciences ◽

10.3390/ijms20051223 ◽

2019 ◽

Vol 20 (5) ◽

pp. 1223 ◽

Cited By ~ 45

Author(s):

Rüdiger Hardeland

Keyword(s):

Amyloid Β ◽

Sirtuin 1 ◽

Toll Like Receptor 4 ◽

System A ◽

Age Related ◽

Microglia Polarization ◽

Inflammatory Phenotype ◽

Secretory Phenotype ◽

Anti Inflammatory ◽

Stimulatory Agent

Aging and various age-related diseases are associated with reductions in melatonin secretion, proinflammatory changes in the immune system, a deteriorating circadian system, and reductions in sirtuin-1 (SIRT1) activity. In non-tumor cells, several effects of melatonin are abolished by inhibiting SIRT1, indicating mediation by SIRT1. Melatonin is, in addition to its circadian and antioxidant roles, an immune stimulatory agent. However, it can act as either a pro- or anti-inflammatory regulator in a context-dependent way. Melatonin can stimulate the release of proinflammatory cytokines and other mediators, but also, under different conditions, it can suppress inflammation-promoting processes such as NO release, activation of cyclooxygenase-2, inflammasome NLRP3, gasdermin D, toll-like receptor-4 and mTOR signaling, and cytokine release by SASP (senescence-associated secretory phenotype), and amyloid-β toxicity. It also activates processes in an anti-inflammatory network, in which SIRT1 activation, upregulation of Nrf2 and downregulation of NF-κB, and release of the anti-inflammatory cytokines IL-4 and IL-10 are involved. A perhaps crucial action may be the promotion of macrophage or microglia polarization in favor of the anti-inflammatory phenotype M2. In addition, many factors of the pro- and anti-inflammatory networks are subject to regulation by microRNAs that either target mRNAs of the respective factors or upregulate them by targeting mRNAs of their inhibitor proteins.

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Roles of programmed death protein 1/programmed death-ligand 1 in secondary brain injury after intracerebral hemorrhage in rats: selective modulation of microglia polarization to anti-inflammatory phenotype

Journal of Neuroinflammation ◽

10.1186/s12974-017-0790-0 ◽

2017 ◽

Vol 14 (1) ◽

Cited By ~ 18

Author(s):

Jie Wu ◽

Liang Sun ◽

Haiying Li ◽

Haitao Shen ◽

Weiwei Zhai ◽

...

Keyword(s):

Brain Injury ◽

Intracerebral Hemorrhage ◽

Secondary Brain Injury ◽

Programmed Death Ligand 1 ◽

Programmed Death ◽

Microglia Polarization ◽

Selective Modulation ◽

Inflammatory Phenotype ◽

Programmed Death Protein 1 ◽

Anti Inflammatory

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Fatty Acid Amide Hydrolase (FAAH) Inhibition Modulates Amyloid-Beta-Induced Microglia Polarization

International Journal of Molecular Sciences ◽

10.3390/ijms22147711 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7711

Author(s):

Maddalena Grieco ◽

Maria Giovanna De Caris ◽

Elisa Maggi ◽

Federica Armeli ◽

Roberto Coccurello ◽

...

Keyword(s):

Fatty Acid Amide Hydrolase ◽

Acid Amide ◽

Protein Activation ◽

Cytoskeleton Reorganization ◽

Microglia Polarization ◽

Inflammatory Phenotype ◽

Faah Inhibition ◽

Anti Inflammatory ◽

Amide Hydrolase ◽

Fatty Acid Amide

The ability of endocannabinoid (eCB) to change functional microglial phenotype can be explored as a possible target for therapeutic intervention. Since the inhibition of fatty acid amide hydrolase (FAAH), the main catabolic enzyme of anandamide (AEA), may provide beneficial effects in mice model of Alzheimer’s disease (AD)-like pathology, we aimed at determining whether the FAAH inhibitor URB597 might target microglia polarization and alter the cytoskeleton reorganization induced by the amyloid-β peptide (Aβ). The morphological evaluation showed that Aβ treatment increased the surface area of BV-2 cells, which acquired a flat and polygonal morphology. URB597 treatment partially rescued the control phenotype of BV-2 cells when co-incubated with Aβ. Moreover, URB597 reduced both the increase of Rho protein activation in Aβ-treated BV-2 cells and the Aβ-induced migration of BV-2 cells, while an increase of Cdc42 protein activation was observed in all samples. URB597 also increased the number of BV-2 cells involved in phagocytosis. URB597 treatment induced the polarization of microglial cells towards an anti-inflammatory phenotype, as demonstrated by the decreased expression of iNOS and pro-inflammatory cytokines along with the parallel increase of Arg-1 and anti-inflammatory cytokines. Taken together, these data suggest that FAAH inhibition promotes cytoskeleton reorganization, regulates phagocytosis and cell migration processes, thus driving microglial polarization towards an anti-inflammatory phenotype.

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Microvesicles carrying LRP5 induce macrophage polarization to an anti‐inflammatory phenotype

Journal of Cellular and Molecular Medicine ◽

10.1111/jcmm.16723 ◽

2021 ◽

Author(s):

Aureli Luquero ◽

Gemma Vilahur ◽

Javier Crespo ◽

Lina Badimon ◽

Maria Borrell‐Pages

Keyword(s):

Macrophage Polarization ◽

Inflammatory Phenotype ◽

Anti Inflammatory

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Anti-Inflammatory and Immunomodulatory Effects of the Grifola frondosa Natural Compound o-Orsellinaldehyde on LPS-Challenged Murine Primary Glial Cells. Roles of NF-κβ and MAPK

Pharmaceutics ◽

10.3390/pharmaceutics13060806 ◽

2021 ◽

Vol 13 (6) ◽

pp. 806

Author(s):

Sarah Tomas-Hernandez ◽

Jordi Blanco ◽

Santiago Garcia-Vallvé ◽

Gerard Pujadas ◽

María José Ojeda-Montes ◽

...

Keyword(s):

Natural Compound ◽

Underlying Disease ◽

Grifola Frondosa ◽

Beneficial Effects ◽

Inflammatory Conditions ◽

Inflammatory Mechanism ◽

Inflammatory Phenotype ◽

Mice Brain ◽

Anti Inflammatory

In response to foreign or endogenous stimuli, both microglia and astrocytes adopt an activated phenotype that promotes the release of pro-inflammatory mediators. This inflammatory mechanism, known as neuroinflammation, is essential in the defense against foreign invasion and in normal tissue repair; nevertheless, when constantly activated, this process can become detrimental through the release of neurotoxic factors that amplify underlying disease. In consequence, this study presents the anti-inflammatory and immunomodulatory properties of o-orsellinaldehyde, a natural compound found by an in silico approach in the Grifola frondosa mushroom, in astrocytes and microglia cells. For this purpose, primary microglia and astrocytes were isolated from mice brain and cultured in vitro. Subsequently, cells were exposed to LPS in the absence or presence of increasing concentrations of this natural compound. Specifically, the results shown that o-orsellinaldehyde strongly inhibits the LPS-induced inflammatory response in astrocytes and microglia by decreasing nitrite formation and downregulating iNOS and HO-1 expression. Furthermore, in microglia cells o-orsellinaldehyde inhibits NF-κB activation; and potently counteracts LPS-mediated p38 kinase and JNK phosphorylation (MAPK). In this regard, o-orsellinaldehyde treatment also induces a significant cell immunomodulation by repolarizing microglia toward the M2 anti-inflammatory phenotype. Altogether, these results could partially explain the reported beneficial effects of G. frondosa extracts on inflammatory conditions.

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Comparative Phenotypic and Functional Analyses of the Effects of IL-10 or TGF-β on Porcine Macrophages

Animals ◽

10.3390/ani11041098 ◽

2021 ◽

Vol 11 (4) ◽

pp. 1098

Author(s):

Tania Carta ◽

Elisabetta Razzuoli ◽

Floriana Fruscione ◽

Susanna Zinellu ◽

Dionigia Meloni ◽

...

Keyword(s):

Macrophage Polarization ◽

Phagocytic Cells ◽

Mhc Ii ◽

Tnf Α ◽

Regulated Expression ◽

Inflammatory Phenotype ◽

Anti Inflammatory ◽

Functional Analyses ◽

The Impact ◽

Immunosuppressive Cytokines

Macrophages are phagocytic cells involved in maintaining tissue homeostasis and defense against pathogens. Macrophages may be polarized into different functionally specialized subsets. M2c macrophages arise following stimulation with IL-10 or TGF-β and mediate anti-inflammatory and tissue repair functions. M2c macrophages remain poorly characterized in the pig, thus we investigated the impact of these regulatory cytokines on porcine monocyte-derived macrophages (moMΦ). The phenotype and functionality of these cells was characterized though confocal microscopy, flow cytometry, ELISA, and RT-qPCR. Both cytokines induced CD14 and MHC II DR down-regulation and reduced IL-6, TNF-α, and CD14 expression, suggestive of an anti-inflammatory phenotype. Interestingly, neither IL-10 or TGF-β were able to trigger IL-10 induction or release by moMΦ. Differences between these cytokines were observed: stimulation with IL-10, but not TGF-β, induced up-regulation of both CD16 and CD163 on moMΦ. In addition, IL-10 down-regulated expression of IL-1β and IL-12p40 4h post-stimulation and induced a stronger impairment of moMΦ ability to respond to either TLR2 or TLR4 agonists. Overall, our results provide an overview of porcine macrophage polarization by two immunosuppressive cytokines, revealing differences between IL-10 and TGF-β, and reporting some peculiarity of swine, which should be considered in translational studies.

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