38 research outputs found
HIV-1 gp120 influences the expression of microRNAs in human monocyte-derived dendritic cells via STAT3 activation
Background:
MicroRNAs (miRs) are an abundant class of small non-coding RNAs (~22 nt) that reprogram gene ex-
pression by targeting mRNA degradation and translational disruption. An emerging concept implicates miR coup-
ling with transcription factors in myeloid cell development and function, thus contributing to host defense and
inflammation. The important role that these molecules play in the pathogenesis of HIV-1 is only now emerging.
Results:
We provide evidence that exposure of monocyte-derived dendritic cells (MDDCs) to recombinant HIV-1 R5
gp120, but not to CCR5 natural ligand CCL4, influences the expression of a panel of miRs (i.e., miR-21, miR-155 and
miR-181b) regulated by STAT3 and potentially targeting genes belonging to the STAT3 signaling pathway. The
blockage of gp120-induced STAT3 activation impairs gp120 capacity to modulate the expression level of above
mentioned miRs. Predictive analysis of miR putative targets emphasizes that these miRs share common target
genes. Furthermore, gene ontology and pathway enrichment analysis outline that these genes mainly belong to
biological processes related to regulation of transcription, in a complex network of interactions involving pathways
relevant to HIV-DC interaction.
Conclusions:
Overall, these results point to gp120-triggered modulation of miR expression via STAT3 activation as a
novel molecular mechanism exploited by HIV-1 to affect DC biology and thus modulate the immune response
through complex regulatory loops involving, at the same time, miRs and transcription factors
Distinct blood and visceral adipose tissue regulatory T cell and innate lymphocyte profiles characterize obesity and colorectal cancer
Visceral adipose tissue (VAT) is a main site where metabolic and immunologic processes
interplay to regulate, at local and systemic level, the inflammatory status and immune
response. Obesity-associated inflammation and immune dysfunctions are inextricably
linked to tumor but, in spite of intense efforts, the mechanisms underpinning this asso-
ciation remain elusive. In this report, we characterized the profile of VAT-associated and
circulating innate lymphocyte and regulatory T (T
reg
) cell subsets underlying inflammatory
conditions, such as obesity and colorectal cancer (CRC). Analysis of NK, NKT-like,
γδ
T,
and T
reg
cell populations in VAT and blood of healthy lean subjects revealed that CD56
hi
NK and OX40
+
T
reg
cells are more abundant in VAT with respect to blood. Conversely,
CD56
dim
NK and total T
reg
cells are most present in the circulation, while
γδ
T lymphocytes
are uniformly distributed in the two compartments. Interestingly, a reduced frequency
of circulating activated T
reg
cells, and a concomitant preferential enrichment of OX40-
expressing T
reg
cells in VAT, were selectively observed in obese (Ob) subjects, and
directly correlated with body mass index. Likewise, CRC patients were characterized by
a specific enrichment of VAT-associated NKT-like cells. In addition, Ob and CRC-affected
individuals shared a significant reduction of the V
γ
9V
δ
2/
γδ
T cell ratio at systemic level.
The alterations in the relative proportions of T
reg
and NKT-like cells in VAT were found
to correlate with the content of pro- and anti-inflammatory polyunsaturated fatty acids
(PUFA), respectively. Overall, these results provide evidence for distinct alterations of the
immune cell repertoire in the periphery with respect to the VAT microenvironment that
uniquely characterize or are shared by different inflammatory conditions, such as obesity
and CRC, and suggest that VAT PUFA composition may represent one of the factors that
contribute to shape the immune phenotypes
Interleukin-9 regulates macrophage activation in the progressive multiple sclerosis brain
Background: Multiple sclerosis (MS) is an immune-mediated, chronic inflammatory, and demyelinating disease of the central nervous system (CNS). Several cytokines are thought to be involved in the regulation of MS pathogenesis. We recently identified interleukin (IL)-9 as a cytokine reducing inflammation and protecting from neurodegeneration in relapsing-remitting MS patients. However, the expression of IL-9 in CNS, and the mechanisms underlying the effect of IL-9 on CNS infiltrating immune cells have never been investigated. Methods: To address this question, we first analyzed the expression levels of IL-9 in post-mortem cerebrospinal fluid of MS patients and the in situ expression of IL-9 in post-mortem MS brain samples by immunohistochemistry. A complementary investigation focused on identifying which immune cells express IL-9 receptor (IL-9R) by flow cytometry, western blot, and immunohistochemistry. Finally, we explored the effect of IL-9 on IL-9-responsive cells, analyzing the induced signaling pathways and functional properties. Results: We found that macrophages, microglia, and CD4 T lymphocytes were the cells expressing the highest levels of IL-9 in the MS brain. Of the immune cells circulating in the blood, monocytes/macrophages were the most responsive to IL-9. We validated the expression of IL-9R by macrophages/microglia in post-mortem brain sections of MS patients. IL-9 induced activation of signal transducer and activator of transcription (STAT)1, STAT3, and STAT5 and reduced the expression of activation markers, such as CD45, CD14, CD68, and CD11b in inflammatory macrophages stimulated in vitro with lipopolysaccharide and interferon (IFN)-γ. Similarly, in situ the number of activated CD68+ macrophages was significantly reduced in areas with high levels of IL-9. Moreover, in the same conditions, IL-9 increased the secretion of the anti-inflammatory cytokine, transforming growth factor (TGF)-β. Conclusions: These results reveal a new cytokine expressed in the CNS, with a role in the context of MS. We have demonstrated that IL-9 and its receptor are both expressed in CNS. Moreover, we found that IL-9 decreases the activation state and promotes the anti-inflammatory properties of human macrophages. This mechanism may contribute to the beneficial effects of IL-9 that are observed in MS, and may be therapeutically potentiated by modulating IL-9 expression in MS
Interleukin-9 regulates macrophage activation in the progressive multiple sclerosis brain.
BACKGROUND: Multiple sclerosis (MS) is an immune-mediated, chronic inflammatory, and demyelinating disease of the central nervous system (CNS). Several cytokines are thought to be involved in the regulation of MS pathogenesis. We recently identified interleukin (IL)-9 as a cytokine reducing inflammation and protecting from neurodegeneration in relapsing-remitting MS patients. However, the expression of IL-9 in CNS, and the mechanisms underlying the effect of IL-9 on CNS infiltrating immune cells have never been investigated. METHODS: To address this question, we first analyzed the expression levels of IL-9 in post-mortem cerebrospinal fluid of MS patients and the in situ expression of IL-9 in post-mortem MS brain samples by immunohistochemistry. A complementary investigation focused on identifying which immune cells express IL-9 receptor (IL-9R) by flow cytometry, western blot, and immunohistochemistry. Finally, we explored the effect of IL-9 on IL-9-responsive cells, analyzing the induced signaling pathways and functional properties. RESULTS: We found that macrophages, microglia, and CD4 T lymphocytes were the cells expressing the highest levels of IL-9 in the MS brain. Of the immune cells circulating in the blood, monocytes/macrophages were the most responsive to IL-9. We validated the expression of IL-9R by macrophages/microglia in post-mortem brain sections of MS patients. IL-9 induced activation of signal transducer and activator of transcription (STAT)1, STAT3, and STAT5 and reduced the expression of activation markers, such as CD45, CD14, CD68, and CD11b in inflammatory macrophages stimulated in vitro with lipopolysaccharide and interferon (IFN)-γ. Similarly, in situ the number of activated CD68+ macrophages was significantly reduced in areas with high levels of IL-9. Moreover, in the same conditions, IL-9 increased the secretion of the anti-inflammatory cytokine, transforming growth factor (TGF)-β. CONCLUSIONS: These results reveal a new cytokine expressed in the CNS, with a role in the context of MS. We have demonstrated that IL-9 and its receptor are both expressed in CNS. Moreover, we found that IL-9 decreases the activation state and promotes the anti-inflammatory properties of human macrophages. This mechanism may contribute to the beneficial effects of IL-9 that are observed in MS, and may be therapeutically potentiated by modulating IL-9 expression in MS
Bovine lactoferrin-induced CCL1 expression involves distinct receptors in monocyte-derived dendritic cells and their monocyte precursors
Lactoferrin (LF) exhibits a wide range of immunomodulatory activities including modulation of cytokine and chemokine secretion. In this study, we demonstrate that bovine LF (bLF) up-modulates, in a concentration- and time-dependent manner, CCL1 secretion in monocytes (Mo) at the early stage of differentiation toward dendritic cells (DCs), and in fully differentiated immature Mo-derived DCs (MoDCs). In both cell types, up-modulation of CCL1 secretion is an early event following bLF-mediated enhanced accumulation of CCL1 transcripts. Notably, bLF-mediated up-regulation of CCL1 involves the engagement of distinct surface receptors in MoDCs and their Mo precursors. We show that bLF-mediated engagement of CD36 contributes to CCL1 induction in differentiating Mo. Conversely, toll-like receptor (TLR)2 blocking markedly reduces bLF-induced CCL1 production in MoDCs. These findings add further evidence for cell-specific differential responses elicited by bLF through the engagement of distinct TLRs and surface receptors. Furthermore, the different responses observed at early and late stages of Mo differentiation towards DCs may be relevant in mediating bLF effects in specific body districts, where these cell types may be differently represented in physiopathological conditions
Fatty acid metabolism complements glycolysis in th selective regulatory t cell expansion during tumor growth
The tumor microenvironment restrains conventional T cell (Tconv) activation while facilitating the expansion of Tregs. Here we showed that Tregs’ advantage in the tumor milieu relies on supplemental energetic routes involving lipid metabolism. In murine models, tumor-infiltrating Tregs displayed intracellular lipid accumulation, which was attributable to an increased rate of fatty acid (FA) synthesis. Since the relative advantage in glucose uptake may fuel FA synthesis in intratumoral Tregs, we demonstrated that both glycolytic and oxidative metabolism contribute to Tregs’ expansion. We corroborated our data in human tumors showing that Tregs displayed a gene signature oriented toward glycolysis and lipid synthesis. Our data support a model in which signals from the tumor microenvironment induce a circuitry of glycolysis, FA synthesis, and oxidation that confers a preferential proliferative advantage to Tregs, whose targeting might represent a strategy for cancer treatment
Vates operose dierum. I Fasti di Ovidio come poema esiodeo
All'inizio dei Fasti il dio Giano apostrofa il narratore come "vates operosus dierum", con chiaro riferimento alle Opere e Giorni: questa caratterizzazione programmatica invita a leggere tutto il poema calendariale di Ovidio in prospettiva esiodea. In effetti il rapporto con Esiodo, o meglio con la complessa figura di Esiodo costruita dalla cultura ellenistica (come autore, come simbolo letterario, ma anche come edizione del testo), attraversa tutta l'opera e si sviluppa su più livelli: aspetti generali (genere medio e didascalico, vates a contatto col divino, poeta panegiristico), singole scene (in particolare in dialogo con la Teogonia), temi e strutture (un poema calendariale come le Opere e Giorni). In Esiodo i Fasti trovano una voce adatta per cantare le leggende fondative della nuova Roma di Augusto e un modello legittimante per trovar posto nello spazio letterario
Il Miluus di Ovidio: una stella originale e il suo mito esiodeo
Il Miluus descritto nel terzo libro dei Fasti è una stella senza riscontri nell’astronomia antica e anche il mito del suo catasterismo non risulta altrimenti noto. Questo articolo affronta i due problemi in modo unitario, individuando in entrambi il ruolo dell’azione creativa del poeta. A partire da una possibile ambiguità dei parapegmata, Ovidio inventa una stella nuova ed elabora un catasterismo originale sulla base di diversi modelli letterari, in particolare la Teogonia di Esiodo