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1.
Cell ; 184(12): 3205-3221.e24, 2021 06 10.
Artículo en Inglés | MEDLINE | ID: mdl-34015271

RESUMEN

Monoclonal antibodies (mAbs) are a focus in vaccine and therapeutic design to counteract severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants. Here, we combined B cell sorting with single-cell VDJ and RNA sequencing (RNA-seq) and mAb structures to characterize B cell responses against SARS-CoV-2. We show that the SARS-CoV-2-specific B cell repertoire consists of transcriptionally distinct B cell populations with cells producing potently neutralizing antibodies (nAbs) localized in two clusters that resemble memory and activated B cells. Cryo-electron microscopy structures of selected nAbs from these two clusters complexed with SARS-CoV-2 spike trimers show recognition of various receptor-binding domain (RBD) epitopes. One of these mAbs, BG10-19, locks the spike trimer in a closed conformation to potently neutralize SARS-CoV-2, the recently arising mutants B.1.1.7 and B.1.351, and SARS-CoV and cross-reacts with heterologous RBDs. Together, our results characterize transcriptional differences among SARS-CoV-2-specific B cells and uncover cross-neutralizing Ab targets that will inform immunogen and therapeutic design against coronaviruses.


Asunto(s)
Anticuerpos Neutralizantes/inmunología , Linfocitos B/metabolismo , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Anticuerpos Monoclonales/química , Anticuerpos Monoclonales/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/química , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/química , Anticuerpos Antivirales/inmunología , Complejo Antígeno-Anticuerpo/química , Complejo Antígeno-Anticuerpo/metabolismo , Reacciones Antígeno-Anticuerpo , Linfocitos B/citología , Linfocitos B/virología , COVID-19/patología , COVID-19/virología , Microscopía por Crioelectrón , Cristalografía por Rayos X , Perfilación de la Expresión Génica , Humanos , Inmunoglobulina A/inmunología , Región Variable de Inmunoglobulina/química , Región Variable de Inmunoglobulina/genética , Dominios Proteicos/inmunología , Multimerización de Proteína , Estructura Cuaternaria de Proteína , SARS-CoV-2/aislamiento & purificación , SARS-CoV-2/metabolismo , Análisis de Secuencia de ARN , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo
2.
Nat Immunol ; 23(7): 1063-1075, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35668320

RESUMEN

Extracellular acidification occurs in inflamed tissue and the tumor microenvironment; however, a systematic study on how pH sensing contributes to tissue homeostasis is lacking. In the present study, we examine cell type-specific roles of the pH sensor G protein-coupled receptor 65 (GPR65) and its inflammatory disease-associated Ile231Leu-coding variant in inflammation control. GPR65 Ile231Leu knock-in mice are highly susceptible to both bacterial infection-induced and T cell-driven colitis. Mechanistically, GPR65 Ile231Leu elicits a cytokine imbalance through impaired helper type 17 T cell (TH17 cell) and TH22 cell differentiation and interleukin (IL)-22 production in association with altered cellular metabolism controlled through the cAMP-CREB-DGAT1 axis. In dendritic cells, GPR65 Ile231Leu elevates IL-12 and IL-23 release at acidic pH and alters endo-lysosomal fusion and degradation capacity, resulting in enhanced antigen presentation. The present study highlights GPR65 Ile231Leu as a multistep risk factor in intestinal inflammation and illuminates a mechanism by which pH sensing controls inflammatory circuits and tissue homeostasis.


Asunto(s)
Colitis , Receptores Acoplados a Proteínas G , Animales , Colitis/metabolismo , Concentración de Iones de Hidrógeno , Inflamación/metabolismo , Lisosomas/metabolismo , Ratones , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/metabolismo , Células Th17/metabolismo
3.
Cell ; 178(5): 1041-1056, 2019 08 22.
Artículo en Inglés | MEDLINE | ID: mdl-31442399

RESUMEN

The current understanding of inflammatory bowel disease (IBD) pathogenesis implicates a complex interaction between host genetics, host immunity, microbiome, and environmental exposures. Mechanisms gleaned from genetics and molecular pathogenesis offer clues to the critical triggers of mucosal inflammation and guide the development of therapeutic interventions. A complex network of interactions between host genetic factors, microbes, and microbial metabolites governs intestinal homeostasis, making classification and mechanistic dissection of involved pathways challenging. In this Review, we discuss these challenges, areas of active translation, and opportunities for development of next-generation therapies.


Asunto(s)
Enfermedades Inflamatorias del Intestino/patología , Microbiota , Inmunidad Adaptativa , Animales , Bacterias/genética , Bacterias/metabolismo , Productos Biológicos/farmacología , Citocinas/genética , Citocinas/metabolismo , Humanos , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/microbiología , Intestinos/inmunología , Intestinos/microbiología , Microbiota/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo
4.
Cell ; 178(3): 714-730.e22, 2019 07 25.
Artículo en Inglés | MEDLINE | ID: mdl-31348891

RESUMEN

Genome-wide association studies (GWAS) have revealed risk alleles for ulcerative colitis (UC). To understand their cell type specificities and pathways of action, we generate an atlas of 366,650 cells from the colon mucosa of 18 UC patients and 12 healthy individuals, revealing 51 epithelial, stromal, and immune cell subsets, including BEST4+ enterocytes, microfold-like cells, and IL13RA2+IL11+ inflammatory fibroblasts, which we associate with resistance to anti-TNF treatment. Inflammatory fibroblasts, inflammatory monocytes, microfold-like cells, and T cells that co-express CD8 and IL-17 expand with disease, forming intercellular interaction hubs. Many UC risk genes are cell type specific and co-regulated within relatively few gene modules, suggesting convergence onto limited sets of cell types and pathways. Using this observation, we nominate and infer functions for specific risk genes across GWAS loci. Our work provides a framework for interrogating complex human diseases and mapping risk variants to cell types and pathways.


Asunto(s)
Colitis Ulcerosa/patología , Colon/metabolismo , Adulto , Anciano , Anticuerpos Monoclonales/uso terapéutico , Bestrofinas/metabolismo , Antígenos CD8/metabolismo , Estudios de Casos y Controles , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Colon/patología , Enterocitos/citología , Enterocitos/metabolismo , Femenino , Sitios Genéticos , Estudio de Asociación del Genoma Completo , Humanos , Interleucina-17/metabolismo , Masculino , Persona de Mediana Edad , Factores de Riesgo , Linfocitos T/citología , Linfocitos T/metabolismo , Trombospondinas/metabolismo , Factor de Necrosis Tumoral alfa/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Adulto Joven
5.
Cell ; 175(5): 1307-1320.e22, 2018 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-30392957

RESUMEN

In the small intestine, a niche of accessory cell types supports the generation of mature epithelial cell types from intestinal stem cells (ISCs). It is unclear, however, if and how immune cells in the niche affect ISC fate or the balance between self-renewal and differentiation. Here, we use single-cell RNA sequencing (scRNA-seq) to identify MHC class II (MHCII) machinery enrichment in two subsets of Lgr5+ ISCs. We show that MHCII+ Lgr5+ ISCs are non-conventional antigen-presenting cells in co-cultures with CD4+ T helper (Th) cells. Stimulation of intestinal organoids with key Th cytokines affects Lgr5+ ISC renewal and differentiation in opposing ways: pro-inflammatory signals promote differentiation, while regulatory cells and cytokines reduce it. In vivo genetic perturbation of Th cells or MHCII expression on Lgr5+ ISCs impacts epithelial cell differentiation and IEC fate during infection. These interactions between Th cells and Lgr5+ ISCs, thus, orchestrate tissue-wide responses to external signals.


Asunto(s)
Diferenciación Celular , Autorrenovación de las Células , Interleucina-10/metabolismo , Células Madre/citología , Linfocitos T Colaboradores-Inductores/metabolismo , Animales , Diferenciación Celular/efectos de los fármacos , Autorrenovación de las Células/efectos de los fármacos , Citocinas/farmacología , Células Epiteliales/citología , Células Epiteliales/metabolismo , Femenino , Antígenos de Histocompatibilidad Clase II/metabolismo , Sistema Inmunológico/metabolismo , Intestinos/citología , Intestinos/microbiología , Masculino , Ratones , Ratones Endogámicos C57BL , Organoides/citología , Organoides/efectos de los fármacos , Organoides/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Salmonella enterica/patogenicidad , Células Madre/metabolismo , Linfocitos T Colaboradores-Inductores/citología
6.
Immunity ; 56(7): 1681-1698.e13, 2023 07 11.
Artículo en Inglés | MEDLINE | ID: mdl-37301199

RESUMEN

CD4+ T cell responses are exquisitely antigen specific and directed toward peptide epitopes displayed by human leukocyte antigen class II (HLA-II) on antigen-presenting cells. Underrepresentation of diverse alleles in ligand databases and an incomplete understanding of factors affecting antigen presentation in vivo have limited progress in defining principles of peptide immunogenicity. Here, we employed monoallelic immunopeptidomics to identify 358,024 HLA-II binders, with a particular focus on HLA-DQ and HLA-DP. We uncovered peptide-binding patterns across a spectrum of binding affinities and enrichment of structural antigen features. These aspects underpinned the development of context-aware predictor of T cell antigens (CAPTAn), a deep learning model that predicts peptide antigens based on their affinity to HLA-II and full sequence of their source proteins. CAPTAn was instrumental in discovering prevalent T cell epitopes from bacteria in the human microbiome and a pan-variant epitope from SARS-CoV-2. Together CAPTAn and associated datasets present a resource for antigen discovery and the unraveling genetic associations of HLA alleles with immunopathologies.


Asunto(s)
COVID-19 , Aprendizaje Profundo , Humanos , Captano , SARS-CoV-2 , Antígenos HLA , Epítopos de Linfocito T , Péptidos
7.
Immunity ; 56(2): 444-458.e5, 2023 02 14.
Artículo en Inglés | MEDLINE | ID: mdl-36720220

RESUMEN

Crohn's disease (CD) is a chronic gastrointestinal disease that is increasing in prevalence worldwide. CD is multifactorial, involving the complex interplay of genetic, immune, and environmental factors, necessitating a system-level understanding of its etiology. To characterize cell-type-specific transcriptional heterogeneity in active CD, we profiled 720,633 cells from the terminal ileum and colon of 71 donors with varying inflammation status. Our integrated datasets revealed organ- and compartment-specific responses to acute and chronic inflammation; most immune changes were in cell composition, whereas transcriptional changes dominated among epithelial and stromal cells. These changes correlated with endoscopic inflammation, but small and large intestines exhibited distinct responses, which were particularly apparent when focusing on IBD risk genes. Finally, we mapped markers of disease-associated myofibroblast activation and identified CHMP1A, TBX3, and RNF168 as regulators of fibrotic complications. Altogether, our results provide a roadmap for understanding cell-type- and organ-specific differences in CD and potential directions for therapeutic development.


Asunto(s)
Enfermedad de Crohn , Humanos , Transcriptoma , Colon , Íleon , Inflamación/genética , Ubiquitina-Proteína Ligasas/genética
8.
Immunity ; 55(10): 1909-1923.e6, 2022 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-36115338

RESUMEN

Reciprocal interactions between host T helper cells and gut microbiota enforce local immunological tolerance and modulate extra-intestinal immunity. However, our understanding of antigen-specific tolerance to the microbiome is limited. Here, we developed a systematic approach to predict HLA class-II-specific epitopes using the humanized bacteria-originated T cell antigen (hBOTA) algorithm. We identified a diverse set of microbiome epitopes spanning all major taxa that are compatible with presentation by multiple HLA-II alleles. In particular, we uncovered an immunodominant epitope from the TonB-dependent receptor SusC that was universally recognized and ubiquitous among Bacteroidales. In healthy human subjects, SusC-reactive T cell responses were characterized by IL-10-dominant cytokine profiles, whereas in patients with active Crohn's disease, responses were associated with elevated IL-17A. Our results highlight the potential of targeted antigen discovery within the microbiome to reveal principles of tolerance and functional transitions during inflammation.


Asunto(s)
Enfermedad de Crohn , Epítopos Inmunodominantes , Linfocitos T CD4-Positivos , Epítopos de Linfocito T , Humanos , Interleucina-10 , Interleucina-17
9.
Cell ; 159(2): 440-55, 2014 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-25263330

RESUMEN

CRISPR-Cas9 is a versatile genome editing technology for studying the functions of genetic elements. To broadly enable the application of Cas9 in vivo, we established a Cre-dependent Cas9 knockin mouse. We demonstrated in vivo as well as ex vivo genome editing using adeno-associated virus (AAV)-, lentivirus-, or particle-mediated delivery of guide RNA in neurons, immune cells, and endothelial cells. Using these mice, we simultaneously modeled the dynamics of KRAS, p53, and LKB1, the top three significantly mutated genes in lung adenocarcinoma. Delivery of a single AAV vector in the lung generated loss-of-function mutations in p53 and Lkb1, as well as homology-directed repair-mediated Kras(G12D) mutations, leading to macroscopic tumors of adenocarcinoma pathology. Together, these results suggest that Cas9 mice empower a wide range of biological and disease modeling applications.


Asunto(s)
Adenocarcinoma/genética , Modelos Animales de Enfermedad , Genes Supresores de Tumor , Ingeniería Genética/métodos , Neoplasias Pulmonares/genética , Oncogenes , Animales , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Células Dendríticas/metabolismo , Técnicas de Sustitución del Gen , Vectores Genéticos , Lentivirus , Ratones , Ratones Transgénicos
10.
Immunity ; 51(4): 696-708.e9, 2019 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-31618654

RESUMEN

Signaling abnormalities in immune responses in the small intestine can trigger chronic type 2 inflammation involving interaction of multiple immune cell types. To systematically characterize this response, we analyzed 58,067 immune cells from the mouse small intestine by single-cell RNA sequencing (scRNA-seq) at steady state and after induction of a type 2 inflammatory reaction to ovalbumin (OVA). Computational analysis revealed broad shifts in both cell-type composition and cell programs in response to the inflammation, especially in group 2 innate lymphoid cells (ILC2s). Inflammation induced the expression of exon 5 of Calca, which encodes the alpha-calcitonin gene-related peptide (α-CGRP), in intestinal KLRG1+ ILC2s. α-CGRP antagonized KLRG1+ ILC2s proliferation but promoted IL-5 expression. Genetic perturbation of α-CGRP increased the proportion of intestinal KLRG1+ ILC2s. Our work highlights a model where α-CGRP-mediated neuronal signaling is critical for suppressing ILC2 expansion and maintaining homeostasis of the type 2 immune machinery.


Asunto(s)
Péptido Relacionado con Gen de Calcitonina/metabolismo , Inflamación/inmunología , Intestinos/inmunología , Linfocitos/inmunología , Neuropéptidos/metabolismo , Animales , Péptido Relacionado con Gen de Calcitonina/genética , Células Cultivadas , Biología Computacional , Inmunidad Innata , Interleucina-5/genética , Interleucina-5/metabolismo , Lectinas Tipo C/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Neuropéptidos/genética , Receptores Inmunológicos/metabolismo , Análisis de Secuencia de ARN , Transducción de Señal , Análisis de la Célula Individual , Células Th2/inmunología , Transcriptoma , Regulación hacia Arriba
11.
Nature ; 608(7921): 168-173, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35896748

RESUMEN

Multiple studies have established associations between human gut bacteria and host physiology, but determining the molecular mechanisms underlying these associations has been challenging1-3. Akkermansia muciniphila has been robustly associated with positive systemic effects on host metabolism, favourable outcomes to checkpoint blockade in cancer immunotherapy and homeostatic immunity4-7. Here we report the identification of a lipid from A. muciniphila's cell membrane that recapitulates the immunomodulatory activity of A. muciniphila in cell-based assays8. The isolated immunogen, a diacyl phosphatidylethanolamine with two branched chains (a15:0-i15:0 PE), was characterized through both spectroscopic analysis and chemical synthesis. The immunogenic activity of a15:0-i15:0 PE has a highly restricted structure-activity relationship, and its immune signalling requires an unexpected toll-like receptor TLR2-TLR1 heterodimer9,10. Certain features of the phospholipid's activity are worth noting: it is significantly less potent than known natural and synthetic TLR2 agonists; it preferentially induces some inflammatory cytokines but not others; and, at low doses (1% of EC50) it resets activation thresholds and responses for immune signalling. Identifying both the molecule and an equipotent synthetic analogue, its non-canonical TLR2-TLR1 signalling pathway, its immunomodulatory selectivity and its low-dose immunoregulatory effects provide a molecular mechanism for a model of A. muciniphila's ability to set immunological tone and its varied roles in health and disease.


Asunto(s)
Akkermansia , Homeostasis , Inmunidad , Fosfatidiletanolaminas , Akkermansia/química , Akkermansia/citología , Akkermansia/inmunología , Membrana Celular/química , Membrana Celular/inmunología , Citocinas/inmunología , Homeostasis/inmunología , Humanos , Mediadores de Inflamación/síntesis química , Mediadores de Inflamación/química , Mediadores de Inflamación/inmunología , Fosfatidiletanolaminas/síntesis química , Fosfatidiletanolaminas/química , Fosfatidiletanolaminas/inmunología , Relación Estructura-Actividad , Receptor Toll-Like 1/inmunología , Receptor Toll-Like 2/agonistas , Receptor Toll-Like 2/inmunología
13.
Proc Natl Acad Sci U S A ; 121(1): e2307086120, 2024 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-38147543

RESUMEN

The salt-inducible kinases (SIK) 1-3 are key regulators of pro- versus anti-inflammatory cytokine responses during innate immune activation. The lack of highly SIK-family or SIK isoform-selective inhibitors suitable for repeat, oral dosing has limited the study of the optimal SIK isoform selectivity profile for suppressing inflammation in vivo. To overcome this challenge, we devised a structure-based design strategy for developing potent SIK inhibitors that are highly selective against other kinases by engaging two differentiating features of the SIK catalytic site. This effort resulted in SIK1/2-selective probes that inhibit key intracellular proximal signaling events including reducing phosphorylation of the SIK substrate cAMP response element binding protein (CREB) regulated transcription coactivator 3 (CRTC3) as detected with an internally generated phospho-Ser329-CRTC3-specific antibody. These inhibitors also suppress production of pro-inflammatory cytokines while inducing anti-inflammatory interleukin-10 in activated human and murine myeloid cells and in mice following a lipopolysaccharide challenge. Oral dosing of these compounds ameliorates disease in a murine colitis model. These findings define an approach to generate highly selective SIK1/2 inhibitors and establish that targeting these isoforms may be a useful strategy to suppress pathological inflammation.


Asunto(s)
Proteína de Unión a Elemento de Respuesta al AMP Cíclico , Proteínas Serina-Treonina Quinasas , Ratones , Humanos , Animales , Proteínas Serina-Treonina Quinasas/metabolismo , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Citocinas , Inflamación/tratamiento farmacológico , Isoformas de Proteínas , Antiinflamatorios/farmacología , Inmunidad Innata , Factores de Transcripción
14.
Trends Immunol ; 44(7): 499-511, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-37236891

RESUMEN

The human intestinal microbiome has coevolved with its host to establish a stable homeostatic relationship with hallmark features of mutualistic symbioses, yet the mechanistic underpinnings of host-microbiome interactions are incompletely understood. Thus, it is an opportune time to conceive a common framework for microbiome-mediated regulation of immune function. We propose the term conditioned immunity to describe the multifaceted mechanisms by which the microbiome modulates immunity. In this regard, microbial colonization is a conditioning exposure that has durable effects on immune function through the action of secondary metabolites, foreign molecular patterns, and antigens. Here, we discuss how spatial niches impact host exposure to microbial products at the level of dose and timing, which elicit diverse conditioned responses.


Asunto(s)
Microbioma Gastrointestinal , Microbiota , Humanos , Intestinos , Sistema Inmunológico , Simbiosis
15.
Nature ; 578(7796): 527-539, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-32103191

RESUMEN

Inflammatory bowel disease (IBD) is a complex genetic disease that is instigated and amplified by the confluence of multiple genetic and environmental variables that perturb the immune-microbiome axis. The challenge of dissecting pathological mechanisms underlying IBD has led to the development of transformative approaches in human genetics and functional genomics. Here we describe IBD as a model disease in the context of leveraging human genetics to dissect interactions in cellular and molecular pathways that regulate homeostasis of the mucosal immune system. Finally, we synthesize emerging insights from multiple experimental approaches into pathway paradigms and discuss future prospects for disease-subtype classification and therapeutic intervention.


Asunto(s)
Enfermedades Inflamatorias del Intestino/genética , Animales , Citocinas/inmunología , Exoma/genética , Fibrosis/inmunología , Fibrosis/patología , Predisposición Genética a la Enfermedad , Homeostasis , Humanos , Inmunidad Celular , Inmunidad Humoral , Inmunidad Innata , Inmunidad Mucosa/genética , Inmunidad Mucosa/inmunología , Inflamación/inmunología , Inflamación/patología , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/patología , Enfermedades Inflamatorias del Intestino/terapia , Mucosa Intestinal/inmunología , Mucosa Intestinal/microbiología , Análisis de la Célula Individual
16.
PLoS Biol ; 20(1): e3001532, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-35085231

RESUMEN

Chronic inflammation is often associated with the development of tissue fibrosis, but how mesenchymal cell responses dictate pathological fibrosis versus resolution and healing remains unclear. Defining stromal heterogeneity and identifying molecular circuits driving extracellular matrix deposition and remodeling stands to illuminate the relationship between inflammation, fibrosis, and healing. We performed single-cell RNA-sequencing of colon-derived stromal cells and identified distinct classes of fibroblasts with gene signatures that are differentially regulated by chronic inflammation, including IL-11-producing inflammatory fibroblasts. We further identify a transcriptional program associated with trans-differentiation of mucosa-associated fibroblasts and define a functional gene signature associated with matrix deposition and remodeling in the inflamed colon. Our analysis supports a critical role for the metalloprotease Adamdec1 at the interface between tissue remodeling and healing during colitis, demonstrating its requirement for colon epithelial integrity. These findings provide mechanistic insight into how inflammation perturbs stromal cell behaviors to drive fibroblastic responses controlling mucosal matrix remodeling and healing.


Asunto(s)
Proteínas ADAM/inmunología , Colitis/inmunología , Matriz Extracelular/metabolismo , Fibroblastos/inmunología , Mucosa Intestinal/inmunología , Células Madre Mesenquimatosas/inmunología , Proteínas ADAM/deficiencia , Proteínas ADAM/genética , Animales , Diferenciación Celular , Colitis/inducido químicamente , Colitis/genética , Colitis/patología , Colon/inmunología , Colon/patología , Matriz Extracelular/inmunología , Fibroblastos/patología , Fibrosis , Regulación de la Expresión Génica , Humanos , Inflamación , Interleucina-11/genética , Interleucina-11/inmunología , Mucosa Intestinal/patología , Masculino , Células Madre Mesenquimatosas/patología , Ratones , Ratones Endogámicos C57BL , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Dodecil Sulfato de Sodio/administración & dosificación , Transcripción Genética , Transcriptoma , Cicatrización de Heridas/genética , Cicatrización de Heridas/inmunología
17.
Phys Rev Lett ; 132(10): 105201, 2024 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-38518330

RESUMEN

We investigate turbulence in magnetic reconnection jets in the Earth's magnetotail using data from the Magnetospheric Multiscale spacecraft. We show that signatures of a limited inertial range are observed in many reconnection jets. The observed turbulence develops on the timescale of a few ion gyroperiods, resulting in intermittent multifractal energy cascade from the characteristic scale of the jet down to the ion scales. We show that at sub-ion scales, the fluctuations are close to monofractal and predominantly kinetic Alfvén waves. The observed energy transfer rate across the inertial range is ∼10^{8} J kg^{-1} s^{-1}, which is the largest reported for space plasmas so far.

18.
J Am Chem Soc ; 145(43): 23422-23426, 2023 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-37871232

RESUMEN

An systematic phenotypic screen of the mouse gut microbiome for metabolites with an immunomodulatory effect identified Muribaculum intestinale as one of only two members with an oversized effect on T-cell populations. Here we report the identification and characterization of a lipid, MiCL-1, as the responsible metabolite. MiCL-1 is an 18:1-16:0 cardiolipin, whose close relatives are found on concave lipid surfaces of both mammals and bacteria. MiCL-1 was synthesized to confirm the structural analysis and functionally characterized in cell-based assays. It has a highly restrictive structure-activity profile, as its chain-switched analog fails to induce responses in any of our assays. MiCL-1 robustly induces the production of pro-inflammatory cytokines like TNF-α, IL-6, and IL-23, but has no detectable effect on the anti-inflammatory cytokine IL-10. As is the case with other recently discovered immunomodulatory lipids, MiCL-1 requires functional TLR2 and TLR1 but not TLR6 in cell-based assays.


Asunto(s)
Cardiolipinas , Citocinas , Animales , Ratones , Receptor Toll-Like 6/metabolismo , Bacteroidetes , Mamíferos/metabolismo
19.
Phys Rev Lett ; 131(11): 115201, 2023 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-37774258

RESUMEN

We present a statistical analysis of ion distributions in magnetic reconnection jets using data from the Magnetospheric Multiscale spacecraft. Compared with the quiet plasma in which the jet propagates, we often find anisotropic and non-Maxwellian ion distributions in the plasma jets. We observe magnetic field fluctuations associated with unstable ion distributions, but the wave amplitudes are not large enough to scatter ions during the observed travel time of the jet. We estimate that the phase-space diffusion due to chaotic and quasiadiabatic ion motion in the current sheet is sufficiently fast to be the primary process leading to isotropization.

20.
Mol Psychiatry ; 27(3): 1405-1415, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35260802

RESUMEN

A missense mutation (A391T) in SLC39A8 is strongly associated with schizophrenia in genomic studies, though the molecular connection to the brain is unknown. Human carriers of A391T have reduced serum manganese, altered plasma glycosylation, and brain MRI changes consistent with altered metal transport. Here, using a knock-in mouse model homozygous for A391T, we show that the schizophrenia-associated variant changes protein glycosylation in the brain. Glycosylation of Asn residues in glycoproteins (N-glycosylation) was most significantly impaired, with effects differing between regions. RNAseq analysis showed negligible regional variation, consistent with changes in the activity of glycosylation enzymes rather than gene expression. Finally, nearly one-third of detected glycoproteins were differentially N-glycosylated in the cortex, including members of several pathways previously implicated in schizophrenia, such as cell adhesion molecules and neurotransmitter receptors that are expressed across all cell types. These findings provide a mechanistic link between a risk allele and potentially reversible biochemical changes in the brain, furthering our molecular understanding of the pathophysiology of schizophrenia and a novel opportunity for therapeutic development.


Asunto(s)
Proteínas de Transporte de Catión , Esquizofrenia , Animales , Encéfalo/metabolismo , Proteínas de Transporte de Catión/genética , Proteínas de Transporte de Catión/metabolismo , Glicosilación , Manganeso/metabolismo , Ratones , Esquizofrenia/genética
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