Dendritic Cell Differentiation Signals Induce Anti-Inflammatory Properties in Human Adult Microglia

Lambert, Caroline; Desbarats, Julie; Arbour, Nathalie; Hall, Jeffery A.; Olivier, André; Bar‐Or, Amit; Antel, Jack P.

doi:10.4049/jimmunol.181.12.8288

Cited by 44 publications

(41 citation statements)

References 50 publications

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“…Several lines of evidences indicate that pro-inflammatory ability of MDDCs correlates positively with the expression level of CD1a [30], [31], [32]. Our findings document for the first time the property of certain PIs to support generation of CD1a low DCs, which secrete normal levels of TNF-α, and lower amounts of IL-12p70 and IL-15.…”

Section: Discussionsupporting

confidence: 63%

Dendritic Cells/Natural Killer Cross-Talk: A Novel Target for Human Immunodeficiency Virus Type-1 Protease Inhibitors

et al. 2010

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BackgroundHIV-1 Protease Inhibitors, namely PIs, originally designed to inhibit HIV-1 aspartic protease, can modulate the immune response by mechanisms largely unknown, and independent from their activity on viral replication. Here, we analyzed the ability of PIs to interfere with differentiation program of monocytes toward dendritic cell (DCs) lineage, a key process in the inflammatory response.Methodology/Principal FindingsMonocytes from healthy donors were isolated and induced to differentiate in vitro in the presence or absence of saquinavir, ritonavir, nelfinavir, indinavir or amprenavir (sqv, rtv, nlfv, idv, apv, respectively). These drugs demonstrated a differential ability to sustain the generation of immature DCs (iDCs) with an altered phenotype, including low levels of CD1a, CD86, CD36 and CD209. DCs generated in the presence of rtv also failed to acquire the typical phenotype of mature DCs (mDCs), and secreted lower amounts of IL-12 and IL-15. Accordingly, these aberrant mDCs failed to support activation of autologous Natural Killer (NK) cells, and resulted highly susceptible to NK cell-mediated cytotoxicity.Conclusions/SignificanceOur findings uncover novel functional properties of PIs within the DC-NK cell cross-talk, unveiling the heterogeneous ability of members of this class drugs to drive the generation of atypical monocyte-derived DCs (MDDCs) showing an aberrant phenotype, a failure to respond appropriately to bacterial endotoxin, a weak ability to prime autologous NK cells, and a high susceptibility to NK cell killing. These unexpected properties might contribute to limit inflammation and viral spreading in HIV-1 infected patients under PIs treatment, and open novel therapeutical perspectives for this class drugs as immunomodulators in autoimmunity and cancer.

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Section: Discussionsupporting

confidence: 63%

Dendritic Cells/Natural Killer Cross-Talk: A Novel Target for Human Immunodeficiency Virus Type-1 Protease Inhibitors

et al. 2010

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“…However, numerous other inflammatory factors have been detected in the CNS during neuroinflammation. We therefore assessed a range of cytokines (interferon, interleukins and chemokines) with known importance to CNS inflammation [26-28] to see if they induced similar effect to IL-1β and TNFα. The pro-inflammatory mediator IFNγ did not affect astrocyte adhesion, nor did IL-2, IL-4 or GMCSF, which were used as negative controls (Figure 5a).…”

Section: Resultsmentioning

confidence: 99%

Exposure to Inflammatory Cytokines IL-1β and TNFα Induces Compromise and Death of Astrocytes; Implications for Chronic Neuroinflammation

et al. 2013

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BackgroundAstrocytes have critical roles in the human CNS in health and disease. They provide trophic support to neurons and are innate-immune cells with keys roles during states-of-inflammation. In addition, they have integral functions associated with maintaining the integrity of the blood-brain barrier. MethodsWe have used cytometric bead arrays and xCELLigence technology to monitor the to monitor the inflammatory response profiles and astrocyte compromise in real-time under various inflammatory conditions. Responses were compared to a variety of inflammatory cytokines known to be released in the CNS during neuroinflammation. Astrocyte compromise measured by xCELLigence was confirmed using ATP measurements, cleaved caspase 3 expression, assessment of nuclear morphology and cell death. ResultsInflammatory activation (IL-1β or TNFα) of astrocytes results in the transient production of key inflammatory mediators including IL-6, cell surface adhesion molecules, and various leukocyte chemoattractants. Following this phase, the NT2-astrocytes progressively become compromised, which is indicated by a loss of adhesion, appearance of apoptotic nuclei and reduction in ATP levels, followed by DEATH.The earliest signs of astrocyte compromise were observed between 24-48h post cytokine treatment. However, significant cell loss was not observed until at least 72h, where there was also an increase in the expression of cleaved-caspase 3. By 96 hours approximately 50% of the astrocytes were dead, with many of the remaining showing signs of compromise too. Numerous other inflammatory factors were tested, however these effects were only observed with IL-1β or TNFα treatment. ConclusionsHere we reveal direct sensitivity to mediators of the inflammatory milieu. We highlight the power of xCELLigence technology for revealing the early progressive compromise of the astrocytes, which occurs 24-48 hours prior to substantive cell loss. Death induced by IL-1β or TNFα is relevant clinically as these two cytokines are produced by various peripheral tissues and by resident brain cells.

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“…Most DENV receptors are also expressed in microglia under differentiated stimulation conditions 26, 27 . Although our findings demonstrated that DENV infected microglia, the cell receptor(s) required for viral binding and entry during DENV infection is unknown.…”

Section: Discussionmentioning

confidence: 99%

Dengue virus infection increases microglial cell migration

Jhan

Tsai

Chen

et al. 2017

Sci Rep

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Activated microglial cells are present in dengue virus (DENV)-infected brains; however, the possible effects of DENV on microglia remain unclear. Here, we demonstrated DENV caused infection, including viral entry, RNA replication, viral protein expression, and virus release, in the murine microglial cell line BV2. DENV infection caused an increase in the formation of the multipolar phenotype in vitro and in vivo without affecting cell growth and cytotoxicity. DENV infection considerably increased cell motility and disrupting either actin filaments or clathrin retarded such effect. Increase in cell migration was only occurred by DENV infection following a clathrin-regulated endocytosis of DENV entry. Ultraviolet-inactivated DENV did not affect cell migration, and pharmacologically blocking toll-like receptor (TLR) 3 and TLR3-related signaling pathways reduced the DENV-induced increase in cell migration. These results demonstrate an advanced effect of DENV infection on microglial migration via a mechanism involving viral entry, RNA release, and TLR3 signal activation.

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Dendritic Cell Differentiation Signals Induce Anti-Inflammatory Properties in Human Adult Microglia

Cited by 44 publications

References 50 publications

Dendritic Cells/Natural Killer Cross-Talk: A Novel Target for Human Immunodeficiency Virus Type-1 Protease Inhibitors

Dendritic Cells/Natural Killer Cross-Talk: A Novel Target for Human Immunodeficiency Virus Type-1 Protease Inhibitors

Exposure to Inflammatory Cytokines IL-1β and TNFα Induces Compromise and Death of Astrocytes; Implications for Chronic Neuroinflammation

Dengue virus infection increases microglial cell migration

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