The lymphatic system comprises a network of lymphoid tissues and vessels that drains the extracellular compartment of most tissues. During tumor development, lymphatic endothelial cells (LECs) ...substantially expand in response to VEGFR-3 engagement by VEGF-C produced in the tumor microenvironment, a process known as tumor-associated lymphangiogenesis. Lymphatic drainage from the tumor to the draining lymph nodes consequently increases, powering interstitial flow in the tumor stroma. The ability of a tumor to induce and activate lymphatic growth has been positively correlated with metastasis. Much effort has been made to identify genes responsible for tumor-associated lymphangiogenesis. Inhibition of lymphangiogenesis with soluble VEGFR-3 or with specific monoclonal antibodies decreases tumor spread to LNs in rodent models. Importantly, tumor-associated lymphatics do not only operate as tumor cell transporters but also play critical roles in anti-tumor immunity. Therefore, metastatic as well as primary tumor progression can be affected by manipulating tumor-associated lymphatic remodeling or function. Here, we review and discuss our current knowledge on the contribution of LECs immersed in the tumor microenvironment as immunoregulators, as well as a possible functional remodeling of LECs subsets depending on the organ microenvironment.
Helminth parasitic infections are a major global health and social burden. The host defence against helminths such as Nippostrongylus brasiliensis is orchestrated by type 2 cell-mediated immunity. ...Induction of type 2 cytokines, including interleukins (IL) IL-4 and IL-13, induce goblet cell hyperplasia with mucus production, ultimately resulting in worm expulsion. However, the mechanisms underlying the initiation of type 2 responses remain incompletely understood. Here we show that tuft cells, a rare epithelial cell type in the steady-state intestinal epithelium, are responsible for initiating type 2 responses to parasites by a cytokine-mediated cellular relay. Tuft cells have a Th2-related gene expression signature and we demonstrate that they undergo a rapid and extensive IL-4Rα-dependent amplification following infection with helminth parasites, owing to direct differentiation of epithelial crypt progenitor cells. We find that the Pou2f3 gene is essential for tuft cell specification. Pou2f3(-/-) mice lack intestinal tuft cells and have defective mucosal type 2 responses to helminth infection; goblet cell hyperplasia is abrogated and worm expulsion is compromised. Notably, IL-4Rα signalling is sufficient to induce expansion of the tuft cell lineage, and ectopic stimulation of this signalling cascade obviates the need for tuft cells in the epithelial cell remodelling of the intestine. Moreover, tuft cells secrete IL-25, thereby regulating type 2 immune responses. Our data reveal a novel function of intestinal epithelial tuft cells and demonstrate a cellular relay required for initiating mucosal type 2 immunity to helminth infection.
Stromal cells (SCs) are strategically positioned in both lymphoid and nonlymphoid organs to provide a scaffold and orchestrate immunity by modulating immune cell maturation, migration and activation. ...Recent characterizations of SCs have expanded our understanding of their heterogeneity and suggested a functional specialization of distinct SC subsets, further modulated by the microenvironment. Lymph node SCs (LNSCs) have been shown to be particularly important in maintaining immune homeostasis and T cell tolerance. Under inflammation situations, such as viral infections or tumor development, SCs undergo profound changes in their numbers and phenotype and play important roles in contributing to either the activation or the control of T cell immunity. In this review, we highlight the role of SCs located in LNs in shaping peripheral T cell responses in different immune contexts, such as autoimmunity, viral and cancer immunity.
Several clinical observations have shown that Bacillus Calmette-Guérin (BCG) vaccine has beneficial impact on patients suffering from different chronic inflammatory diseases. Here we evaluated ...whether BCG inactivated by Extended Freeze-Drying (EFD) which circumvents all the side effects linked to the live bacteria, could influence the development of experimental autoimmune encephalomyelitis (EAE), a mouse model for Multiple Sclerosis. EFD BCG strongly attenuates inflammation, both systemically and at the central nervous system (CNS) level, alleviating EAE. Mechanistically, EFD BCG directly impacts the phenotype of plasmacytoid dendritic cells (pDCs), and promotes their ability to induce suppressive IL-10 secreting regulatory T cells (Tregs) that inhibit encephalitogenic CD4
T cells. When co-cultured with human allogenic naive CD4
T cells, EFD BCG exposed human pDCs similarly induce the differentiation of IL-10 producing Tregs. Our study provides evidence that EFD BCG could be used as an immunomodulator of encephalitogenic T cells in multiple sclerosis patients.
The way we build cities generates considerable volumes of excavated soil. This transfer of soil from the city to the outlying rural areas causes tensions. The financial windfall from the removal and ...storage of these soils is countered by problems of social and environmental acceptance in the receiving areas. We analyse the mechanisms at work in the production of excavated soils before looking at the counterpart of this economy in rural areas while seeking to understand the logic behind the selection of areas as outlets for excavated soils and inert materials. Awareness of this geography involving a profound physical modification of the landscapes concerned encourages us to look for new ways of relating to urban soils and their use in landscape projects. This raises the question of how landscape architects may support this transformation in the management of urban soils, from the production to the reception of excavated soils.
Background
Endogenous opioids, including enkephalins, are fundamental regulators of pain. In inflammatory conditions, the local release of opioids by leukocytes at the inflammatory site inhibits ...nociceptor firing, thereby inducing analgesia. Accordingly, in chronic intestinal T
h
1/T
h
17-associated inflammation, enkephalins released by colitogenic CD4
+
T lymphocytes relieve inflammation-induced visceral pain. The present study aims to investigate whether mucosal T-cell-derived enkephalins also exhibit a potent anti-inflammatory activity as described for exogenous opioid drugs in T
h
1/T
h
17-associated colitis.
Methods
The anti-inflammatory effects of endogenous opioids were investigated in both T
h
1/T
h
17-associated (transfer of CD4
+
CD45RB
high
T lymphocytes) and T
h
2-associated (oxazolone) colitis models in mice. Inflammation-induced colonic damage and CD4
+
T cell subsets were compared in mice treated or not treated with naloxone methiodide, a peripheral antagonist of opioid receptors. The anti-inflammatory activity of T-cell-derived enkephalins was further estimated by comparison of colitis severity in immunodeficient mice into which naïve CD4
+
CD45RB
high
T lymphocytes originating from wild-type or enkephalin-knockout mice had been transferred.
Results
Peripheral opioid receptor blockade increases the severity of T
h
1/T
h
17-induced colitis and attenuates T
h
2 oxazolone colitis. The opposite effects of naloxone methiodide treatment in these two models of intestinal inflammation are dependent on the potency of endogenous opioids to promote a T
h
2-type immune response. Accordingly, the transfer of enkephalin-deficient CD4
+
CD45RB
high
T lymphocytes into immunodeficient mice exacerbates inflammation-induced colonic injury.
Conclusions
Endogenous opioids, including T-cell-derived enkephalins, promote a T
h
2-type immune response, which, depending on the context, may either attenuate (T
h
1/T
h
17-associated) or aggravate (T
h
2-associated) intestinal inflammation.
A growing body of evidence from basic and clinical studies supports the therapeutic potential of estrogens in multiple sclerosis (MS), originating from the well-established reduction in relapse rates ...observed among women with MS during pregnancy. The biological effects of estrogens are mediated by estrogen receptors (ERα and ERβ). Estrogens or selective ER-agonists have been shown to exert potent neuroprotective or anti-inflammatory effects in experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. A central question in EAE is to identify the cellular targets that express a functional ER isotype, and the mechanisms underlying the neuroprotective and anti-inflammatory effects of estrogens. Using pharmacological approaches targeting ER-specific functions, and genetic tools such as conditional knockout mice in which ERα or ERβ are selectively deleted in specific cell populations, a clearer picture is now emerging of the various cellular targets and downstream molecules responsible for estrogen-mediated protection against central nervous system autoimmunity.
The CNS has traditionally been considered an immune‐privileged organ, but recent studies have identified a plethora of immune cells in the choroid plexus, meninges, perivascular spaces, and ...cribriform plate. Although those immune cells are crucial for the maintenance of CNS homeostasis and for neural protection against infections, they can lead to neuroinflammation in some circumstances. The blood and the lymphatic vasculatures exhibit distinct structural and molecular features depending on their location in the CNS, greatly influencing the compartmentalization and the nature of CNS immune responses. In this review, we discuss how endothelial cells regulate the migration and the functions of T cells in the CNS both at steady‐state and in murine models of neuroinflammation, with a special focus on the anatomical, cellular, and molecular mechanisms implicated in EAE.
Immune cells are present in various CNS locations and contribute to neuroinflammation. The article reviews the role of endothelial cells on T‐cell migration and functions, emphasizing the anatomical and molecular mechanisms involved in experimental autoimmune encephalomyelitis, and exploring the complex interplay between immune responses and CNS vasculature.
Limited information is available regarding the cellular mechanisms of oxaliplatin-induced painful neuropathy during exposure of patients to this drug. We therefore determined oxidative stress in ...cultured cells and evaluated its occurrence in C57BL/6 mice. Using both cultured neuroblastoma (SH-SY5Y) and macrophage (RAW 264.7) cell lines and also brain tissues of oxaliplatin-treated mice, we investigated whether oxaliplatin (OXA) induces oxidative stress and apoptosis. Cultured cells were treated with 2-200 µM OXA for 24 h. The effects of pharmacological inhibitors of oxidative stress or inflammation (N-acetyl cysteine, ibuprofen, acetaminophen) were also tested. Inhibitors were added 30 min before OXA treatment and then in combination with OXA for 24 h. In SH-SY5Y cells, OXA caused a significant dose-dependent decrease in viability, a large increase in ROS and NO production, lipid peroxidation and mitochondrial impairment as assessed by a drop in mitochondrial membrane potential, which are deleterious for the cell. An increase in levels of negatively charged phospholipids such as cardiolipin but also phosphatidylserine and phosphatidylinositol, was also observed. Additionally, OXA caused concentration-dependent P2X7 receptor activation, increased chromatin condensation and caspase-3 activation associated with TNF-α and IL-6 release. The majority of these toxic effects were equally observed in Raw 264.7 which also presented high levels of PGE2. Pretreatment of SH-SY5Y cells with pharmacological inhibitors significantly reduced or blocked all the neurotoxic OXA effects. In OXA-treated mice (28 mg/kg cumulated dose) significant cold hyperalgesia and oxidative stress in the tested brain areas were shown. Our study suggests that targeting P2X7 receptor activation and mitochondrial impairment might be a potential therapeutic strategy against OXA-induced neuropathic pain.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
During tumor development, the tumor microenvironment impacts negatively anti-tumor T cell responses. Indeed tumors develop mechanisms to avoid immunosurveillance by inducing poorly immunogenic tumors ...or by setting up tolerogenic mechanisms to inhibit effective immune responses. In the context of lymphangiogenic tumors, lymphatic endothelial cells (LECs) substantially expand in the tumor itself and in the tumor draining lymph node, resulting in increased lymphatic drainage, tumor cell dissemination and metastasis. Recently, LECs have been given much attention as putative unconventional antigen presenting cells.
Our group and others have studied their immunoregulatory role, pointing out their contribution in adaptive immunity. Previous studies have demonstrated that LECs can directly present tumor-derived antigens to tumor-specific CD8+ T cells leading to their deletion. However, it is unknown whether LECs can directly present tumor antigens to CD4+ T cells. Using a murine tumor cell line that promotes lymphangiogenesis, we show that, when MHCII expression is abrogated in LEC, tumor growth is reduced, effector T cell functions are enhanced, whereas the phenotype of suppressive regulatory T cells seems to be impaired. These results suggest that tumor-associated LECs would function as tolerogenic antigen-presenting cells, a property that could be blocked to improve immunotherapies in cancer. Further experiments will be performed in order to confirm these results, and extend to a mouse model of non-small cell lung cancer which is initiated by transformation of normal cells and is more physiologically relevant to humans.
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