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1.
Front Immunol ; 14: 1071553, 2023.
Article in English | MEDLINE | ID: mdl-37143680

ABSTRACT

Th1 and Th17 cell migration into the central nervous system (CNS) is a fundamental process in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Particularly, leptomeningeal vessels of the subarachnoid space (SAS) constitute a central route for T cell entry into the CNS during EAE. Once migrated into the SAS, T cells show an active motility behavior, which is a prerequisite for cell-cell communication, in situ reactivation and neuroinflammation. However, the molecular mechanisms selectively controlling Th1 and Th17 cell trafficking in the inflamed leptomeninges are not well understood. By using epifluorescence intravital microscopy, we obtained results showing that myelin-specific Th1 and Th17 cells have different intravascular adhesion capacity depending on the disease phase, with Th17 cells being more adhesive at disease peak. Inhibition of αLß2 integrin selectively blocked Th1 cell adhesion, but had no effect on Th17 rolling and arrest capacity during all disease phases, suggesting that distinct adhesion mechanisms control the migration of key T cell populations involved in EAE induction. Blockade of α4 integrins affected myelin-specific Th1 cell rolling and arrest, but only selectively altered intravascular arrest of Th17 cells. Notably, selective α4ß7 integrin blockade inhibited Th17 cell arrest without interfering with intravascular Th1 cell adhesion, suggesting that α4ß7 integrin is predominantly involved in Th17 cell migration into the inflamed leptomeninges in EAE mice. Two-photon microscopy experiments showed that blockade of α4 integrin chain or α4ß7 integrin selectively inhibited the locomotion of extravasated antigen-specific Th17 cells in the SAS, but had no effect on Th1 cell intratissue dynamics, further pointing to α4ß7 integrin as key molecule in Th17 cell trafficking during EAE development. Finally, therapeutic inhibition of α4ß7 integrin at disease onset by intrathecal injection of a blocking antibody attenuated clinical severity and reduced neuroinflammation, further demonstrating a crucial role for α4ß7 integrin in driving Th17 cell-mediated disease pathogenesis. Altogether, our data suggest that a better knowledge of the molecular mechanisms controlling myelin-specific Th1 and Th17 cell trafficking during EAE delevopment may help to identify new therapeutic strategies for CNS inflammatory and demyelinating diseases.


Subject(s)
Encephalomyelitis, Autoimmune, Experimental , Mice , Animals , Th17 Cells , Neuroinflammatory Diseases , Spinal Cord/pathology , Integrins/metabolism , Integrin alpha4
2.
Front Immunol ; 10: 2436, 2019.
Article in English | MEDLINE | ID: mdl-31681316

ABSTRACT

Leukocyte trafficking is a key event during autoimmune and inflammatory responses. The subarachnoid space (SAS) and cerebrospinal fluid are major routes for the migration of encephalitogenic T cells into the central nervous system (CNS) during experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis, and are sites of T cell activation before the invasion of CNS parenchyma. In particular, autoreactive Th1 and Th17 cell trafficking and reactivation in the CNS are required for the pathogenesis of EAE. However, the molecular mechanisms controlling T cell dynamics during EAE are unclear. We used two-photon laser microscopy to show that autoreactive Th1 and Th17 cells display distinct motility behavior within the SAS in the spinal cords of mice immunized with the myelin oligodendrocyte glycoprotein peptide MOG35-55. Th1 cells showed a strong directional bias at the disease peak, moving in a straight line and covering long distances, whereas Th17 cells exhibited more constrained motility. The dynamics of both Th1 and Th17 cells were strongly affected by blocking the integrin LFA-1, which interfered with the deformability and biomechanics of Th1 but not Th17 cells. The intrathecal injection of a blocking anti-LFA-1 antibody at the onset of disease significantly inhibited EAE progression and also strongly reduced neuro-inflammation in the immunized mice. Our results show that LFA-1 plays a pivotal role in T cell motility during EAE and suggest that interfering with the molecular mechanisms controlling T cell motility can help to reduce the pathogenic potential of autoreactive lymphocytes.


Subject(s)
Cell Movement/immunology , Central Nervous System/immunology , Inflammation/immunology , Lymphocyte Function-Associated Antigen-1/immunology , Th1 Cells/immunology , Th17 Cells/immunology , Animals , Cell Movement/genetics , Central Nervous System/metabolism , Central Nervous System/pathology , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/genetics , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/metabolism , Female , Gene Expression Profiling/methods , Humans , Inflammation/genetics , Inflammation/metabolism , Lymphocyte Activation/genetics , Lymphocyte Activation/immunology , Lymphocyte Function-Associated Antigen-1/genetics , Lymphocyte Function-Associated Antigen-1/metabolism , Mice, Inbred C57BL , Mice, Transgenic , Microscopy, Confocal/methods , Multiple Sclerosis/genetics , Multiple Sclerosis/immunology , Multiple Sclerosis/metabolism , Myelin-Oligodendrocyte Glycoprotein/immunology , Peptide Fragments/immunology , Spinal Cord/immunology , Spinal Cord/metabolism , Spinal Cord/pathology , Th1 Cells/metabolism , Th17 Cells/metabolism
3.
Front Immunol ; 8: 211, 2017.
Article in English | MEDLINE | ID: mdl-28303140

ABSTRACT

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the progressive deterioration of cognitive functions. Its neuropathological features include amyloid-ß (Aß) accumulation, the formation of neurofibrillary tangles, and the loss of neurons and synapses. Neuroinflammation is a well-established feature of AD pathogenesis, and a better understanding of its mechanisms could facilitate the development of new therapeutic approaches. Recent studies in transgenic mouse models of AD have shown that neutrophils adhere to blood vessels and migrate inside the parenchyma. Moreover, studies in human AD subjects have also shown that neutrophils adhere and spread inside brain vessels and invade the parenchyma, suggesting these cells play a role in AD pathogenesis. Indeed, neutrophil depletion and the therapeutic inhibition of neutrophil trafficking, achieved by blocking LFA-1 integrin in AD mouse models, significantly reduced memory loss and the neuropathological features of AD. We observed that neutrophils release neutrophil extracellular traps (NETs) inside blood vessels and in the parenchyma of AD mice, potentially harming the blood-brain barrier and neural cells. Furthermore, confocal microscopy confirmed the presence of NETs inside the cortical vessels and parenchyma of subjects with AD, providing more evidence that neutrophils and NETs play a role in AD-related tissue destruction. The discovery of NETs inside the AD brain suggests that these formations may exacerbate neuro-inflammatory processes, promoting vascular and parenchymal damage during AD. The inhibition of NET formation has achieved therapeutic benefits in several models of chronic inflammatory diseases, including autoimmune diseases affecting the brain. Therefore, the targeting of NETs may delay AD pathogenesis and offer a novel approach for the treatment of this increasingly prevalent disease.

4.
Nat Med ; 21(8): 880-6, 2015 Aug.
Article in English | MEDLINE | ID: mdl-26214837

ABSTRACT

Inflammation is a pathological hallmark of Alzheimer's disease, and innate immune cells have been shown to contribute to disease pathogenesis. In two transgenic models of Alzheimer's disease (5xFAD and 3xTg-AD mice), neutrophils extravasated and were present in areas with amyloid-ß (Aß) deposits, where they released neutrophil extracellular traps (NETs) and IL-17. Aß42 peptide triggered the LFA-1 integrin high-affinity state and rapid neutrophil adhesion to integrin ligands. In vivo, LFA-1 integrin controlled neutrophil extravasation into the CNS and intraparenchymal motility. In transgenic Alzheimer's disease models, neutrophil depletion or inhibition of neutrophil trafficking via LFA-1 blockade reduced Alzheimer's disease-like neuropathology and improved memory in mice already showing cognitive dysfunction. Temporary depletion of neutrophils for 1 month at early stages of disease led to sustained improvements in memory. Transgenic Alzheimer's disease model mice lacking LFA-1 were protected from cognitive decline and had reduced gliosis. In humans with Alzheimer's disease, neutrophils adhered to and spread inside brain venules and were present in the parenchyma, along with NETs. Our results demonstrate that neutrophils contribute to Alzheimer's disease pathogenesis and cognitive impairment and suggest that the inhibition of neutrophil trafficking may be beneficial in Alzheimer's disease.


Subject(s)
Alzheimer Disease/etiology , Cognition Disorders/etiology , Lymphocyte Function-Associated Antigen-1/physiology , Neutrophils/physiology , Alzheimer Disease/pathology , Amyloid beta-Peptides/physiology , Animals , Cell Adhesion , Cell Movement , Extracellular Traps , Humans , Interleukin-17/biosynthesis , Mice , Mice, Inbred C57BL , Mice, Transgenic , Peptide Fragments/physiology
5.
Immunity ; 40(4): 542-53, 2014 Apr 17.
Article in English | MEDLINE | ID: mdl-24703780

ABSTRACT

Selectins play a central role in leukocyte trafficking by mediating tethering and rolling on vascular surfaces. Here we have reported that T cell immunoglobulin and mucin domain 1 (TIM-1) is a P-selectin ligand. We have shown that human and murine TIM-1 binds to P-selectin, and that TIM-1 mediates tethering and rolling of T helper 1 (Th1) and Th17, but not Th2 and regulatory T cells on P-selectin. Th1 and Th17 cells lacking the TIM-1 mucin domain showed reduced rolling in thrombin-activated mesenteric venules and inflamed brain microcirculation. Inhibition of TIM-1 had no effect on naive T cell homing, but it reduced T cell recruitment in a skin hypersensitivity model and blocked experimental autoimmune encephalomyelitis. Uniquely, the TIM-1 immunoglobulin variable domain was also required for P-selectin binding. Our data demonstrate that TIM-1 is a major P-selectin ligand with a specialized role in T cell trafficking during inflammatory responses and the induction of autoimmune disease.


Subject(s)
Brain/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Hypersensitivity/immunology , Membrane Proteins/metabolism , P-Selectin/metabolism , T-Lymphocyte Subsets/immunology , Th1 Cells/immunology , Adoptive Transfer , Animals , Cell Movement/genetics , Cell Proliferation , Cells, Cultured , Hepatitis A Virus Cellular Receptor 1 , Ligands , Membrane Glycoproteins/genetics , Membrane Proteins/genetics , Membrane Proteins/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Myelin-Oligodendrocyte Glycoprotein/immunology , Peptide Fragments/immunology
6.
J Immunol ; 191(11): 5489-500, 2013 Dec 01.
Article in English | MEDLINE | ID: mdl-24174617

ABSTRACT

Regulatory T cells (Tregs) maintain tolerance toward self-antigens and suppress autoimmune diseases, although the underlying molecular mechanisms are unclear. In this study, we show that mice deficient for P-selectin glycoprotein ligand-1 (PSGL-1) develop a more severe form of experimental autoimmune encephalomyelitis than wild type animals do, suggesting that PSGL-1 has a role in the negative regulation of autoimmunity. We found that Tregs lacking PSGL-1 were unable to suppress experimental autoimmune encephalomyelitis and failed to inhibit T cell proliferation in vivo in the lymph nodes. Using two-photon laser-scanning microscopy in the lymph node, we found that PSGL-1 expression on Tregs had no role in the suppression of early T cell priming after immunization with Ag. Instead, PSGL-1-deficient Tregs lost the ability to modulate T cell movement and failed to inhibit the T cell-dendritic cell contacts and T cell clustering essential for sustained T cell activation during the late phase of the immune response. Notably, PSGL-1 expression on myelin-specific effector T cells had no role in T cell locomotion in the lymph node. Our data show that PSGL-1 represents a previously unknown, phase-specific mechanism for Treg-mediated suppression of the persistence of immune responses and autoimmunity induction.


Subject(s)
Dendritic Cells/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Membrane Glycoproteins/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Regulatory/immunology , Animals , Cell Communication/genetics , Cell Growth Processes/genetics , Cell Movement/genetics , Cells, Cultured , Disease Progression , Female , Humans , Lymph Nodes/pathology , Lymphocyte Activation/genetics , Membrane Glycoproteins/genetics , Membrane Glycoproteins/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Myelin Sheath/immunology
7.
J Mol Neurosci ; 40(3): 342-52, 2010 Mar.
Article in English | MEDLINE | ID: mdl-19862643

ABSTRACT

The role of insulin-like growth factor 1 (IGF1) pathway as regulator of aging and age-related diseases is increasingly recognized. Recent evidence has been provided that neuronal IGF1-R increases during aging leading to activation of a signaling pathway that causes an increased production of amyloid beta-peptide, the principal event in the pathogenesis of Alzheimer's disease. Here, by using long-term neuronal cultures as a model of aging, we show that astroglial cells are required to upregulate the expression of IGF1-R in neurons during in vitro senescence. Moreover, evidence is provided that the cross-talk between astrocytes and neurons is independent of cell-to-cell contact, and it is mediated by low molecular weight soluble factor(s) released by astrocytes in culture medium. These results suggest that astrocytes could play an important role in aging and age-related pathological processes.


Subject(s)
Aging/physiology , Astrocytes/metabolism , Cerebral Cortex/cytology , Neurons/metabolism , Receptor, IGF Type 1/metabolism , Animals , Astrocytes/cytology , Cells, Cultured , Cerebral Cortex/physiology , Coculture Techniques , Culture Media, Conditioned/metabolism , Neurons/cytology , Rats , Rats, Sprague-Dawley , Signal Transduction/physiology
8.
Exp Cell Res ; 311(1): 126-34, 2005 Nov 15.
Article in English | MEDLINE | ID: mdl-16223482

ABSTRACT

In this paper, evidence is provided that p75 neurotrophin receptor (p75NTR) exerts an opposite role on the cytotoxic function of beta-amyloid (Abeta) depending on the different state of the peptide, fibrillar or oligomeric soluble form. Previous work in our laboratory has shown that the expression of p75NTR is required for cell death in vitro by Abeta peptides in fibrillar form (G. Perini, V. Della-Bianca, V. Politi, G. Della Valle, I. Dal-Pra, F. Rossi, U. Armato. Role of p75 neurotrophin receptor in the neurotoxicity by beta-amyloid peptides and synergistic effect of inflammatory cytokines. J. Exp. Med. 195 (2002) 907-918). In the present study, performed by using the same cell clones and procedures as in previous paper, we show that: (a) soluble oligomers of Abeta(1-42) exert a cytotoxic activity independent of p75NTR, (b) the expression of p75NTR exerts a protective role against the toxic activity of soluble oligomers, (c) this role is due to an active function of the juxtamembrane sequence of the cytoplasmic region of p75NTR and (d) the protective function is mediated by phosphatidylinositide 3-kinase (PI3K) activity.


Subject(s)
Amyloid beta-Peptides/toxicity , Neuroblastoma/drug therapy , Peptide Fragments/toxicity , Receptor, Nerve Growth Factor/metabolism , Caspases/metabolism , Cell Death/drug effects , Cell Proliferation/drug effects , Cytoprotection , Dimerization , Humans , Mutation , Neuroblastoma/metabolism , Neuroblastoma/pathology , Phosphatidylinositol 3-Kinases/metabolism , Tumor Cells, Cultured
9.
J Mol Neurosci ; 25(2): 141-56, 2005.
Article in English | MEDLINE | ID: mdl-15784962

ABSTRACT

The accumulation of beta-amyloid (Abeta) peptide is a key pathogenic event in Alzheimer's disease. Previous studies have shown that Abeta peptide can damage neurons by activating the p75 neurotrophin receptor (p75NTR). However, the signaling pathway leading to neuronal cell death is not completely understood. By using a neuroblastoma cell line devoid of neurotrophin receptors and engineered to express either a full-length or a death domain (DD)-truncated form of p75NTR, we demonstrated that Abeta peptide activates the mitogen-activated protein kinases (MAPKs) p38 and c-Jun N-terminal kinase (JNK). We also found that Abeta peptide induces the translocation of nuclear factor-kappaB (NF-kappaB). These events depend on the DD of p75NTR. Beta-amyloid (Abeta) peptide was found not to be toxic when the above interactors were inhibited, indicating that they are required for Abeta-induced neuronal cell death. p75 neurotrophin receptor (p75NTR)-expressing cells became resistant to Abeta toxicity when transfected with dominant-negative mutants of MAPK kinases 3, 4, or 6 (MKK3, MKK4, or MKK6), the inhibitor of kappaBalpha, or when treated with chemical inhibitors of p38 and JNK. Furthermore, p75NTR-expressing cells became resistant to Abeta peptide upon transfection with a dominant-negative mutant of p53. These results were obtained in the presence of normal p38 and JNK activation, indicating that p53 acts downstream of p38 and JNK. Finally, we demonstrated that NF-kappaB activation is dependent on p38 and JNK activation. Therefore, our data suggest a signaling pathway in which Abeta peptide binds to p75NTR and activates p38 and JNK in a DD-dependent manner, followed by NF-kappaB translocation and p53 activation.


Subject(s)
Amyloid beta-Peptides/metabolism , Cell Death/physiology , Neurons/cytology , Receptor, Nerve Growth Factor/metabolism , Signal Transduction/physiology , Cell Line, Tumor , Humans , JNK Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/metabolism , Neuroblastoma , Neurons/metabolism , Receptor, Nerve Growth Factor/genetics , Tumor Suppressor Protein p53/metabolism , p38 Mitogen-Activated Protein Kinases/metabolism
10.
J Exp Med ; 195(7): 907-18, 2002 Apr 01.
Article in English | MEDLINE | ID: mdl-11927634

ABSTRACT

The neurodegenerative changes in Alzheimer's disease (AD) are elicited by the accumulation of beta-amyloid peptides (Abeta), which damage neurons either directly by interacting with components of the cell surface to trigger cell death signaling or indirectly by activating astrocytes and microglia to produce inflammatory mediators. It has been recently proposed that the p75 neurotrophin receptor (p75(NTR)) is responsible for neuronal damage by interacting with Abeta. By using neuroblastoma cell clones lacking the expression of all neurotrophin receptors or engineered to express full-length or various truncated forms of p75(NTR), we could show that p75(NTR) is involved in the direct signaling of cell death by Abeta via the function of its death domain. This signaling leads to the activation of caspases-8 and -3, the production of reactive oxygen intermediates and the induction of an oxidative stress. We also found that the direct and indirect (inflammatory) mechanisms of neuronal damage by Abeta could act synergistically. In fact, TNF-alpha and IL-1beta, cytokines produced by Abeta-activated microglia, could potentiate the neurotoxic action of Abeta mediated by p75(NTR) signaling. Together, our results indicate that neurons expressing p75(NTR), mostly if expressing also proinflammatory cytokine receptors, might be preferential targets of the cytotoxic action of Abeta in AD.


Subject(s)
Amyloid beta-Peptides/toxicity , Cell Survival/drug effects , Cytokines/toxicity , Neurons/drug effects , Neurotoxins/toxicity , Receptors, Nerve Growth Factor/physiology , Clone Cells , Drug Synergism , Gene Expression Regulation , Humans , Kinetics , Neuroblastoma , Neurons/pathology , Peptide Fragments/toxicity , Receptor, Nerve Growth Factor , Receptor, trkA/genetics , Receptor, trkA/physiology , Receptors, Nerve Growth Factor/drug effects , Receptors, Nerve Growth Factor/genetics , Recombinant Proteins/metabolism , Sequence Deletion , Transfection , Tumor Cells, Cultured
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