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1.
Nat Immunol ; 22(5): 639-653, 2021 05.
Artículo en Inglés | MEDLINE | ID: mdl-33907320

RESUMEN

White adipose tissue (WAT) is an essential regulator of energy storage and systemic metabolic homeostasis. Regulatory networks consisting of immune and structural cells are necessary to maintain WAT metabolism, which can become impaired during obesity in mammals. Using single-cell transcriptomics and flow cytometry, we unveil a large-scale comprehensive cellular census of the stromal vascular fraction of healthy lean and obese human WAT. We report new subsets and developmental trajectories of adipose-resident innate lymphoid cells, dendritic cells and monocyte-derived macrophage populations that accumulate in obese WAT. Analysis of cell-cell ligand-receptor interactions and obesity-enriched signaling pathways revealed a switch from immunoregulatory mechanisms in lean WAT to inflammatory networks in obese WAT. These results provide a detailed and unbiased cellular landscape of homeostatic and inflammatory circuits in healthy human WAT.


Asunto(s)
Inmunidad Innata , Obesidad/inmunología , Grasa Subcutánea Abdominal/inmunología , Abdominoplastia , Adipocitos/inmunología , Adipocitos/metabolismo , Adulto , Comunicación Celular/inmunología , Línea Celular , Células Dendríticas Foliculares/inmunología , Células Dendríticas Foliculares/metabolismo , Femenino , Humanos , Inflamación/inmunología , Inflamación/patología , Linfocitos/inmunología , Linfocitos/metabolismo , Macrófagos/inmunología , Macrófagos/metabolismo , Obesidad/patología , Obesidad/cirugía , RNA-Seq , Transducción de Señal/inmunología , Análisis de la Célula Individual , Grasa Subcutánea Abdominal/patología , Grasa Subcutánea Abdominal/cirugía
2.
Nat Immunol ; 20(8): 1004-1011, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31263280

RESUMEN

Innate lymphoid cells (ILCs) are tissue-resident sentinels that are essential for early host protection from pathogens at initial sites of infection. However, whether pathogen-derived antigens directly modulate the responses of tissue-resident ILCs has remained unclear. In the present study, it was found that liver-resident type 1 ILCs (ILC1s) expanded locally and persisted after the resolution of infection with mouse cytomegalovirus (MCMV). ILC1s acquired stable transcriptional, epigenetic and phenotypic changes a month after the resolution of MCMV infection, and showed an enhanced protective effector response to secondary challenge with MCMV consistent with a memory lymphocyte response. Memory ILC1 responses were dependent on the MCMV-encoded glycoprotein m12, and were independent of bystander activation by proinflammatory cytokines after heterologous infection. Thus, liver ILC1s acquire adaptive features in an MCMV-specific manner.


Asunto(s)
Memoria Inmunológica/inmunología , Hígado/inmunología , Linfocitos/inmunología , Glicoproteínas de Membrana/inmunología , Muromegalovirus/inmunología , Proteínas del Envoltorio Viral/inmunología , Animales , Infecciones por Herpesviridae/inmunología , Infecciones por Herpesviridae/virología , Inmunidad Innata/inmunología , Subunidad alfa del Receptor de Interleucina-18/metabolismo , Hígado/citología , Ratones
3.
Immunity ; 52(1): 96-108.e9, 2020 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-31810881

RESUMEN

Although type 1 innate lymphoid cells (ILC1s) have been originally found as liver-resident ILCs, their pathophysiological role in the liver remains poorly investigated. Here, we demonstrated that carbon tetrachloride (CCl4) injection into mice activated ILC1s, but not natural killer (NK) cells, in the liver. Activated ILC1s produced interferon-γ (IFN-γ) and protected mice from CCl4-induced acute liver injury. IFN-γ released from activated ILC1s promoted the survival of hepatocytes through upregulation of Bcl-xL. An activating NK receptor, DNAM-1, was required for the optimal activation and IFN-γ production of liver ILC1s. Extracellular adenosine triphosphate accelerated interleukin-12-driven IFN-γ production by liver ILC1s. These findings suggest that ILC1s are critical for tissue protection during acute liver injury.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Hepatocitos/metabolismo , Interferón gamma/inmunología , Hígado/citología , Linfocitos/inmunología , Proteína bcl-X/metabolismo , Adenosina Trifosfato/metabolismo , Animales , Antígenos de Diferenciación de Linfocitos T/genética , Antígenos de Diferenciación de Linfocitos T/metabolismo , Tetracloruro de Carbono/toxicidad , Células Cultivadas , Femenino , Subunidad p35 de la Interleucina-12/inmunología , Células Asesinas Naturales/inmunología , Hígado/inmunología , Hígado/lesiones , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados
4.
Drug Dev Res ; 81(1): 43-51, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31483516

RESUMEN

Bacteriocins, the ribosomally produced antimicrobial peptides of bacteria, represent an untapped source of promising antibiotic alternatives. However, bacteriocins display diverse mechanisms of action, a narrow spectrum of activity, and inherent challenges in natural product isolation making in vitro verification of putative bacteriocins difficult. A subset of bacteriocins exert their antimicrobial effects through favorable biophysical interactions with the bacterial membrane mediated by the charge, hydrophobicity, and conformation of the peptide. We have developed a pipeline for bacteriocin-derived compound design and testing that combines sequence-free prediction of bacteriocins using machine learning and a simple biophysical trait filter to generate 20 amino acid peptides that can be synthesized and evaluated for activity. We generated 28,895 total 20-mer candidate peptides and scored them for charge, α-helicity, and hydrophobic moment. Of those, we selected 16 sequences for synthesis and evaluated their antimicrobial, cytotoxicity, and hemolytic activities. Peptides with the overall highest scores for our biophysical parameters exhibited significant antimicrobial activity against Escherichia coli and Pseudomonas aeruginosa. Our combined method incorporates machine learning and biophysical-based minimal region determination to create an original approach to swiftly discover bacteriocin candidates amenable to rapid synthesis and evaluation for therapeutic use.


Asunto(s)
Antibacterianos/síntesis química , Péptidos Catiónicos Antimicrobianos/síntesis química , Bacteriocinas/química , Biología Computacional/métodos , Antibacterianos/química , Antibacterianos/farmacología , Péptidos Catiónicos Antimicrobianos/química , Péptidos Catiónicos Antimicrobianos/farmacología , Diseño de Fármacos , Escherichia coli/efectos de los fármacos , Escherichia coli/crecimiento & desarrollo , Interacciones Hidrofóbicas e Hidrofílicas , Aprendizaje Automático , Pruebas de Sensibilidad Microbiana , Dominios Proteicos , Estructura Secundaria de Proteína , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/crecimiento & desarrollo , Staphylococcus aureus/efectos de los fármacos , Staphylococcus aureus/crecimiento & desarrollo , Relación Estructura-Actividad
5.
Cell Rep ; 42(2): 112141, 2023 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-36807146

RESUMEN

Tissue-resident immune cells are critical to the initiation and potentiation of inflammation. However, the tissue-protective cellular communication networks initiated by resident immunity during sterile inflammation are not well understood. Using single-cell transcriptomic analysis, we show the liver-resident cell connectome and signalome during acute liver injury. These analyses identify Il12b as a central regulator of liver injury-associated changes in gene expression. Interleukin (IL)-12 produced by conventional type 1 dendritic cells (cDC1s) is required for protection during acute injury through activation of interferon (IFN)-γ production by liver-resident type 1 innate lymphoid cells (ILC1s). Using a targeted in vivo CRISPR-Cas9 screen of innate immune sensing pathways, we find that cDC1-intrinsic cGAS-STING signaling acts upstream of IL-12 production to initiate early protective immune responses. Our study identifies the core communication hubs initiated by tissue-resident innate immune cells during sterile inflammation in vivo and implicates cDC1-derived IL-12 as an important regulator of this process.


Asunto(s)
Inmunidad Innata , Linfocitos , Humanos , Linfocitos/metabolismo , Hígado/metabolismo , Inflamación , Nucleotidiltransferasas/metabolismo , Interleucina-12
6.
Nat Metab ; 5(12): 2237-2252, 2023 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-37996702

RESUMEN

Obesity is associated with chronic low-grade white adipose tissue (WAT) inflammation that can contribute to the development of insulin resistance in mammals. Previous studies have identified interleukin (IL)-12 as a critical upstream regulator of WAT inflammation and metabolic dysfunction during obesity. However, the cell types and mechanisms that initiate WAT IL-12 production remain unclear. Here we show that conventional type 1 dendritic cells (cDC1s) are the cellular source of WAT IL-12 during obesity through analysis of mouse and human WAT single-cell transcriptomic datasets, IL-12 reporter mice and IL-12p70 protein levels by enzyme-linked immunosorbent assay. We demonstrate that cDC1s contribute to obesity-associated inflammation by increasing group 1 innate lymphocyte interferon-γ production and inflammatory macrophage accumulation. Inducible depletion of cDC1s increased WAT insulin sensitivity and systemic glucose tolerance during diet-induced obesity. Mechanistically, endocytosis of apoptotic bodies containing self-DNA by WAT cDC1s drives stimulator of interferon genes (STING)-dependent IL-12 production. Together, these results suggest that WAT cDC1s act as critical regulators of adipose tissue inflammation and metabolic dysfunction during obesity.


Asunto(s)
Resistencia a la Insulina , Obesidad , Animales , Humanos , Obesidad/metabolismo , Tejido Adiposo/metabolismo , Adiposidad/genética , Inflamación/metabolismo , Interleucina-12/metabolismo , Mamíferos/metabolismo
7.
STAR Protoc ; 1(3): 100113, 2020 12 18.
Artículo en Inglés | MEDLINE | ID: mdl-33377009

RESUMEN

CRISPR-Cas9 genome engineering can be used to functionally investigate the complex mechanisms of immune system regulation. Decades of work have aimed to genetically reprogram innate immunity, but current approaches are inefficient or nonspecific, limiting their use. Here, we detail an optimized strategy for non-viral CRISPR-Cas9 ribonucleoprotein (cRNP) genomic editing of primary innate lymphocytes (ILCs) and myeloid lineage cells, resulting in high-efficiency editing of target gene expression from a single electroporation. For complete details on the use and execution of this protocol, please refer to Riggan et al. (2020).


Asunto(s)
Electroporación/métodos , Edición Génica/métodos , Inmunidad Innata/genética , Animales , Sistemas CRISPR-Cas/genética , Genómica , Humanos , Inmunidad Innata/fisiología , Linfocitos/metabolismo , Células Mieloides/metabolismo , Ribonucleoproteínas/genética , Ribonucleoproteínas/metabolismo
8.
Cell Rep ; 31(7): 107651, 2020 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-32433960

RESUMEN

CRISPR genome engineering has become a powerful tool to functionally investigate the complex mechanisms of immune system regulation. While decades of work have aimed to genetically reprogram innate immunity, the utility of current approaches is restricted by poor knockout efficiencies or limited specificity for mature cell lineages in vivo. Here, we describe an optimized strategy for non-viral CRISPR-Cas9 ribonucleoprotein (cRNP) genomic editing of mature primary mouse innate lymphocyte cells (ILCs) and myeloid lineage cells that results in an almost complete loss of single or double target gene expression from a single electroporation. Furthermore, we describe in vivo adoptive transfer mouse models that can be utilized to screen for gene function during viral infection using cRNP-edited naive natural killer (NK) cells and bone-marrow-derived conventional dendritic cell precursors (cDCPs). This resource will enhance target gene discovery and offer a specific and simplified approach to gene editing in the mouse innate immune system.


Asunto(s)
Edición Génica/métodos , Terapia Genética/métodos , Inmunidad Innata/genética , Ribonucleoproteínas/metabolismo , Animales , Sistemas CRISPR-Cas , Ratones
9.
Viruses ; 11(3)2019 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-30893756

RESUMEN

Infection is restrained by the concerted activation of tissue-resident and circulating immune cells. Recent discoveries have demonstrated that tissue-resident lymphocyte subsets, comprised of innate lymphoid cells (ILCs) and unconventional T cells, have vital roles in the initiation of primary antiviral responses. Via direct and indirect mechanisms, ILCs and unconventional T cell subsets play a critical role in the ability of the immune system to mount an effective antiviral response through potent early cytokine production. In this review, we will summarize the current knowledge of tissue-resident lymphocytes during initial viral infection and evaluate their redundant or nonredundant contributions to host protection or virus-induced pathology.


Asunto(s)
Inmunidad Innata , Tejido Linfoide/citología , Subgrupos de Linfocitos T/inmunología , Virosis/inmunología , Animales , Diferenciación Celular/inmunología , Ensayos Clínicos como Asunto , Modelos Animales de Enfermedad , Humanos , Tejido Linfoide/inmunología , Ratones
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