RESUMEN
Tumors weakly infiltrated by T lymphocytes poorly respond to immunotherapy. We aimed to unveil malignancy-associated programs regulating T cell entrance, arrest, and activation in the tumor environment. Differential expression of cell adhesion and tissue architecture programs, particularly the presence of the membrane tetraspanin claudin (CLDN)18 as a signature gene, demarcated immune-infiltrated from immune-depleted mouse pancreatic tumors. In human pancreatic ductal adenocarcinoma (PDAC) and non-small cell lung cancer, CLDN18 expression positively correlated with more differentiated histology and favorable prognosis. CLDN18 on the cell surface promoted accrual of cytotoxic T lymphocytes (CTLs), facilitating direct CTL contacts with tumor cells by driving the mobilization of the adhesion protein ALCAM to the lipid rafts of the tumor cell membrane through actin. This process favored the formation of robust immunological synapses (ISs) between CTLs and CLDN18-positive cancer cells, resulting in increased T cell activation. Our data reveal an immune role for CLDN18 in orchestrating T cell infiltration and shaping the tumor immune contexture.
Asunto(s)
Carcinoma Ductal Pancreático , Claudinas , Activación de Linfocitos , Neoplasias Pancreáticas , Linfocitos T Citotóxicos , Animales , Humanos , Ratones , Carcinoma de Pulmón de Células no Pequeñas/inmunología , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/patología , Carcinoma Ductal Pancreático/metabolismo , Línea Celular Tumoral , Claudinas/metabolismo , Claudinas/genética , Regulación Neoplásica de la Expresión Génica/inmunología , Sinapsis Inmunológicas/metabolismo , Sinapsis Inmunológicas/inmunología , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Activación de Linfocitos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Microdominios de Membrana/metabolismo , Microdominios de Membrana/inmunología , Ratones Endogámicos C57BL , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Linfocitos T Citotóxicos/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
BACKGROUND AIMS: Adipose mesenchymal stem cells (ASCs) represent a promising therapeutic approach in inflammatory neurological disorders, including multiple sclerosis (MS). Recent lines of evidence indicate that most biological activities of ASCs are mediated by the delivery of soluble factors enclosed in extracellular vesicles (EVs). Indeed, we have previously demonstrated that small EVs derived from ASCs (ASC-EVs) ameliorate experimental autoimmune encephalomyelitis (EAE), a murine model of MS. The precise mechanisms and molecular/cellular target of EVs during EAE are still unknown. METHODS: To investigate the homing of ASC-EVs, we intravenously injected small EVs loaded with ultra-small superparamagnetic iron oxide nanoparticles (USPIO) at disease onset in EAE-induced C57Bl/6J mice. Histochemical analysis and transmission electron microscopy were carried out 48 h after EV treatment. Moreover, to assess the cellular target of EVs, flow cytometry on cells extracted ex vivo from EAE mouse lymph nodes was performed. RESULTS: Histochemical and ultrastructural analysis showed the presence of labeled EVs in lymph nodes but not in lungs and spinal cord of EAE injected mice. Moreover, we identified the cellular target of EVs in EAE lymph nodes by flow cytometry: ASC-EVs were preferentially located in macrophages, with a consistent amount also noted in dendritic cells and CD4+ T lymphocytes. CONCLUSIONS: This represents the first direct evidence of the privileged localization of ASC-EVs in draining lymph nodes of EAE after systemic injection. These data provide prominent information on the distribution, uptake and retention of ASC-EVs, which may help in the development of EV-based therapy in MS.
Asunto(s)
Encefalomielitis Autoinmune Experimental , Vesículas Extracelulares , Células Madre Mesenquimatosas , Esclerosis Múltiple , Ratones , Animales , Encefalomielitis Autoinmune Experimental/terapia , Encefalomielitis Autoinmune Experimental/patología , Esclerosis Múltiple/terapia , Esclerosis Múltiple/patología , Ganglios Linfáticos , Ratones Endogámicos C57BLRESUMEN
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.
Asunto(s)
Encéfalo/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Hipersensibilidad/inmunología , Proteínas de la Membrana/metabolismo , Selectina-P/metabolismo , Subgrupos de Linfocitos T/inmunología , Células TH1/inmunología , Traslado Adoptivo , Animales , Movimiento Celular/genética , Proliferación Celular , Células Cultivadas , Receptor Celular 1 del Virus de la Hepatitis A , Ligandos , Glicoproteínas de Membrana/genética , Proteínas de la Membrana/genética , Proteínas de la Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Glicoproteína Mielina-Oligodendrócito/inmunología , Fragmentos de Péptidos/inmunologíaAsunto(s)
COVID-19 , Vacunas contra el Cáncer , Neoplasias , Humanos , Inmunoterapia , Neoplasias/terapiaAsunto(s)
Vacunas contra el Cáncer , Neoplasias , Terapia Biológica , Humanos , Inmunoterapia , Italia , Neoplasias/terapiaRESUMEN
RATIONALE: Cystic fibrosis (CF) is a common genetic disease caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Persistent lung inflammation, characterized by increasing polymorphonuclear leukocyte recruitment, is a major cause of the decline in respiratory function in patients with CF and is a leading cause of morbidity and mortality. CFTR is expressed in various cell types, including leukocytes, but its involvement in the regulation of leukocyte recruitment is unknown. OBJECTIVES: We evaluated whether CF leukocytes might present with alterations in cell adhesion and migration, a key process governing innate and acquired immune responses. METHODS: We used ex vivo adhesion and chemotaxis assays, flow cytometry, immunofluorescence, and GTPase activity assays in this study. MEASUREMENTS AND MAIN RESULTS: We found that chemoattractant-induced activation of ß1 and ß2 integrins and of chemotaxis is defective in mononuclear cells isolated from patients with CF. In contrast, polymorphonuclear leukocyte adhesion and chemotaxis were normal. The functionality of ß1 and ß2 integrins was restored by treatment of CF monocytes with the CFTR-correcting drugs VRT325 and VX809. Moreover, treatment of healthy monocytes with the CFTR inhibitor CFTR(inh)-172 blocked integrin activation by chemoattractants. In a murine model of lung inflammation, we found that integrin-independent migration of CF monocytes into the lung parenchyma was normal, whereas, in contrast, integrin-dependent transmigration into the alveolar space was impaired. Finally, signal transduction analysis showed that, in CF monocytes, chemoattractant-triggered activation of RhoA and CDC42 Rho small GTPases (controlling integrin activation and chemotaxis, respectively) was strongly deficient. CONCLUSIONS: Altogether, these data highlight the critical regulatory role of CFTR in integrin activation by chemoattractants in monocytes and identify CF as a new, cell type-selective leukocyte adhesion deficiency disease, providing new insights into CF pathogenesis.
Asunto(s)
Adhesión Celular/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Leucocitos/metabolismo , Monocitos/metabolismo , Mutación/genética , Animales , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Modelos Animales de Enfermedad , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Humanos , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
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.
Asunto(s)
Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Glicoproteínas de Membrana/metabolismo , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Animales , Comunicación Celular/genética , Procesos de Crecimiento Celular/genética , Movimiento Celular/genética , Células Cultivadas , Progresión de la Enfermedad , Femenino , Humanos , Ganglios Linfáticos/patología , Activación de Linfocitos/genética , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Vaina de Mielina/inmunologíaRESUMEN
Pattern recognition receptors are primitive sensors that arouse a preconfigured immune response to broad stimuli, including nonself pathogen-associated and autologous damage-associated molecular pattern molecules. These receptors are mainly expressed by innate myeloid cells, including granulocytes, monocytes, macrophages, and dendritic cells. Recent investigations have revealed new insights into these receptors as key players not only in triggering inflammation processes against pathogen invasion but also in mediating immune suppression in specific pathological states, including cancer. Myeloid-derived suppressor cells are preferentially expanded in many pathological conditions. This heterogeneous cell population includes immunosuppressive myeloid cells that are thought to be associated with poor prognosis and impaired response to immune therapies in various cancers. Identification of pattern recognition receptors and their ligands increases the understanding of immune-activating and immune-suppressive myeloid cell functions and sheds light on myeloid-derived suppressor cell differences from cognate granulocytes and monocytes in healthy conditions. This review summarizes the different expression, ligand recognition, signaling pathways, and cancer relations and identifies Toll-like receptors as potential new targets on myeloid-derived suppressor cells in cancer, which might help us to decipher the instruction codes for reverting suppressive myeloid cells toward an antitumor phenotype.
Asunto(s)
Células Supresoras de Origen Mieloide , Neoplasias , Sesamum , Células Mieloides , Receptores de Reconocimiento de PatronesRESUMEN
Autoinflammatory disorders and autoimmune diseases result from abnormal deviations of innate and adaptive immunity that heterogeneously affect organs and clinical phenotypes. Despite having etiologic and phenotypic differences, these two conditions share the onset of an aberrant inflammatory process. Targeting the main drivers controlling inflammation is useful to treat both autoimmune and autoinflammatory syndromes. TNF-α is a major player in the inflammatory immune response, and anti-TNF-α antibodies have been a revolutionary treatment in many autoimmune disorders. However, production difficulties and high development costs hinder their implementation, and accessibility to their use is still limited. Innovative strategies aimed at overcoming the limitations associated with anti-TNF-α antibodies are being explored, including RNA-based therapies. Here we summarize the central role of TNF-α in immune disorders and how anti-TNF-based immunotherapies changed the therapeutic landscape, albeit with important limitations related to side effects, tolerance, and resistance to therapies. We then outline how nanotechnology has provided the final momentum for the use of nucleic acids in the treatment of autoimmune and autoinflammatory diseases, with a focus on inflammatory bowel diseases (IBDs). The example of IBDs allows the evaluation and discussion of the nucleic acids-based treatments that have been developed, to identify the role that innovative approaches possess in view of the treatment of autoinflammatory disorders and autoimmune diseases.
Asunto(s)
Enfermedades Autoinmunes , Productos Biológicos , Enfermedades Inflamatorias del Intestino , Humanos , Factor de Necrosis Tumoral alfa/uso terapéutico , Productos Biológicos/uso terapéutico , ARN , Nanomedicina , Inhibidores del Factor de Necrosis Tumoral/uso terapéutico , Enfermedades Autoinmunes/tratamiento farmacológico , Factores Biológicos/uso terapéutico , Inflamación , Enfermedades Inflamatorias del Intestino/tratamiento farmacológicoRESUMEN
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.
Asunto(s)
Encefalomielitis Autoinmune Experimental , Ratones , Animales , Células Th17 , Enfermedades Neuroinflamatorias , Médula Espinal/patología , Integrinas/metabolismo , Integrina alfa4RESUMEN
Cancer cells favor the generation of myeloid cells with immunosuppressive and inflammatory features, including myeloid-derived suppressor cells (MDSCs), which support tumor progression. The anti-apoptotic molecule, cellular FLICE (FADD-like interleukin-1ß-converting enzyme)-inhibitory protein (c-FLIP), which acts as an important modulator of caspase-8, is required for the development and function of monocytic (M)-MDSCs. Here, we assessed the effect of immune checkpoint inhibitor (ICI) therapy on systemic immunological landscape, including FLIP-expressing MDSCs, in non-small cell lung cancer (NSCLC) patients. Longitudinal changes in peripheral immunological parameters were correlated with patients' outcome. In detail, 34 NSCLC patients were enrolled and classified as progressors (P) or non-progressors (NP), according to the RECIST evaluation. We demonstrated a reduction in pro-inflammatory cytokines such as IL-8, IL-6, and IL-1ß in only NP patients after ICI treatment. Moreover, using t-distributed stochastic neighbor embedding (t-SNE) and cluster analysis, we characterized in NP patients a significant increase in the amount of lymphocytes and a slight contraction of myeloid cells such as neutrophils and monocytes. Despite this moderate ICI-associated alteration in myeloid cells, we identified a distinctive reduction of c-FLIP expression in M-MDSCs from NP patients concurrently with the first clinical evaluation (T1), even though NP and P patients showed the same level of expression at baseline (T0). In agreement with the c-FLIP expression, monocytes isolated from both P and NP patients displayed similar immunosuppressive functions at T0; however, this pro-tumor activity was negatively influenced at T1 in the NP patient cohort exclusively. Hence, ICI therapy can mitigate systemic inflammation and impair MDSC-dependent immunosuppression.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Células Supresoras de Origen Mieloide , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Monocitos , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológicoRESUMEN
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive decline associated with the deposition of amyloid-ß (Aß) plaques, hyperphosphorylation of tau protein, and neuronal loss. Vascular inflammation and leukocyte trafficking may contribute to AD pathogenesis, and a better understanding of these inflammation mechanisms could therefore facilitate the development of new AD therapies. Here we show that T cells extravasate in the proximity of cerebral VCAM-1+ vessels in 3xTg-AD transgenic mice, which develop both Aß and tau pathologies. The counter-ligand of VCAM-1 - α4ß1 integrin, also known as very late antigen-4 (VLA-4) - was more abundant on circulating CD4+ T cells and was also expressed by a significant proportion of blood CD8+ T cells and neutrophils in AD mice. Intravital microscopy of the brain microcirculation revealed that α4 integrins control leukocyte-endothelial interactions in AD mice. Therapeutic targeting of VLA-4 using antibodies that specifically block α4 integrins improved the memory of 3xTg-AD mice compared to an isotype control. These antibodies also reduced neuropathological hallmarks of AD, including microgliosis, Aß load and tau hyperphosphorylation. Our results demonstrate that α4 integrin-dependent leukocyte trafficking promotes cognitive impairment and AD neuropathology, suggesting that the blockade of α4 integrins may offer a new therapeutic strategy in AD.
Asunto(s)
Enfermedad de Alzheimer/etiología , Enfermedad de Alzheimer/metabolismo , Comunicación Celular , Endotelio/metabolismo , Integrina alfa4/antagonistas & inhibidores , Leucocitos/metabolismo , Memoria , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/tratamiento farmacológico , Péptidos beta-Amiloides/metabolismo , Animales , Anticuerpos Monoclonales/farmacología , Biomarcadores , Modelos Animales de Enfermedad , Regulación de la Expresión Génica , Inmunohistoquímica , Integrina alfa4/genética , Integrina alfa4/metabolismo , Aprendizaje por Laberinto , Ratones , Ratones Transgénicos , Placa Amiloide/metabolismo , Placa Amiloide/patología , Resultado del Tratamiento , Proteínas tau/metabolismoRESUMEN
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.
Asunto(s)
Movimiento Celular/inmunología , Sistema Nervioso Central/inmunología , Inflamación/inmunología , Antígeno-1 Asociado a Función de Linfocito/inmunología , Células TH1/inmunología , Células Th17/inmunología , Animales , Movimiento Celular/genética , Sistema Nervioso Central/metabolismo , Sistema Nervioso Central/patología , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/genética , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Inflamación/genética , Inflamación/metabolismo , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Antígeno-1 Asociado a Función de Linfocito/genética , Antígeno-1 Asociado a Función de Linfocito/metabolismo , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Confocal/métodos , Esclerosis Múltiple/genética , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Glicoproteína Mielina-Oligodendrócito/inmunología , Fragmentos de Péptidos/inmunología , Médula Espinal/inmunología , Médula Espinal/metabolismo , Médula Espinal/patología , Células TH1/metabolismo , Células Th17/metabolismoRESUMEN
Cell based-therapies represent promising strategies for the treatment of neurological diseases. We have previously shown that adipose stem cells (ASC) ameliorate chronic experimental autoimmune encephalomyelitis (EAE). Recent evidence indicates that most ASC paracrine effects are mediated by extracellular vesicles, i.e. micro- and nanovesicles (MVs and NVs). We show that preventive intravenous administration of NVs isolated from ASC (ASC-NVs) before disease onset significantly reduces the severity of EAE and decreases spinal cord inflammation and demyelination, whereas therapeutic treatment with ASC-NVs does not ameliorate established EAE. This treatment marginally inhibits antigen-specific T cell activation, while reducing microglial activation and demyelination in the spinal cord. Importantly, ASC-NVs inhibited integrin-dependent adhesion of encephalitogenic T cells in vitro, with no effect on adhesion molecule expression. In addition, intravital microscopy showed that encephalitogenic T cells treated with ASC NVs display a significantly reduced rolling and firm adhesion in inflamed spinal cord vessels compared to untreated cells. Our results show that ASC-NVs ameliorate EAE pathogenesis mainly by inhibiting T cell extravasation in the inflamed CNS, suggesting that NVs may represent a novel therapeutic approach in neuro-inflammatory diseases, enabling the safe administration of ASC effector factors.
Asunto(s)
Tejido Adiposo/citología , Encefalomielitis Autoinmune Experimental/terapia , Vesículas Extracelulares/fisiología , Células Madre Mesenquimatosas/citología , Linfocitos T/fisiología , Animales , Movimiento Celular/inmunología , Células Cultivadas , Enfermedad Crónica , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Vesículas Extracelulares/trasplante , Trasplante de Células Madre Mesenquimatosas/métodos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Linfocitos T/patologíaRESUMEN
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.