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1.
Nature ; 600(7887): 158-163, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34819667

RESUMEN

Endogenous DNA damage can perturb transcription, triggering a multifaceted cellular response that repairs the damage, degrades RNA polymerase II and shuts down global transcription1-4. This response is absent in the human disease Cockayne syndrome, which is caused by loss of the Cockayne syndrome A (CSA) or CSB proteins5-7. However, the source of endogenous DNA damage and how this leads to the prominent degenerative features of this disease remain unknown. Here we find that endogenous formaldehyde impedes transcription, with marked physiological consequences. Mice deficient in formaldehyde clearance (Adh5-/-) and CSB (Csbm/m; Csb is also known as Ercc6) develop cachexia and neurodegeneration, and succumb to kidney failure, features that resemble human Cockayne syndrome. Using single-cell RNA sequencing, we find that formaldehyde-driven transcriptional stress stimulates the expression of the anorexiogenic peptide GDF15 by a subset of kidney proximal tubule cells. Blocking this response with an anti-GDF15 antibody alleviates cachexia in Adh5-/-Csbm/m mice. Therefore, CSB provides protection to the kidney and brain against DNA damage caused by endogenous formaldehyde, while also suppressing an anorexic endocrine signal. The activation of this signal might contribute to the cachexia observed in Cockayne syndrome as well as chemotherapy-induced anorectic weight loss. A plausible evolutionary purpose for such a response is to ensure aversion to genotoxins in food.


Asunto(s)
Síndrome de Cockayne , Daño del ADN , Formaldehído/efectos adversos , Estrés Fisiológico/efectos de los fármacos , Transcripción Genética/efectos de los fármacos , Alcohol Deshidrogenasa/deficiencia , Alcohol Deshidrogenasa/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Caquexia/complicaciones , Síndrome de Cockayne/inducido químicamente , Síndrome de Cockayne/complicaciones , Síndrome de Cockayne/genética , Síndrome de Cockayne/patología , Enzimas Reparadoras del ADN/deficiencia , Modelos Animales de Enfermedad , Femenino , Formaldehído/metabolismo , Factor 15 de Diferenciación de Crecimiento/antagonistas & inhibidores , Factor 15 de Diferenciación de Crecimiento/biosíntesis , Factor 15 de Diferenciación de Crecimiento/genética , Túbulos Renales Proximales/efectos de los fármacos , Túbulos Renales Proximales/metabolismo , Túbulos Renales Proximales/patología , Masculino , Ratones , Proteínas de Unión a Poli-ADP-Ribosa/deficiencia , Insuficiencia Renal/complicaciones , Transcripción Genética/genética
2.
Am J Respir Crit Care Med ; 207(5): 566-576, 2023 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-36095143

RESUMEN

Rationale: Obesity affects 40% of U.S. adults, is associated with a proinflammatory state, and presents a significant risk factor for the development of severe coronavirus disease (COVID-19). To date, there is limited information on how obesity might affect immune cell responses in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Objectives: To determine the impact of obesity on respiratory tract immunity in COVID-19 across the human lifespan. Methods: We analyzed single-cell transcriptomes from BAL in three ventilated adult cohorts with (n = 24) or without (n = 9) COVID-19 from nasal immune cells in children with (n = 14) or without (n = 19) COVID-19, and from peripheral blood mononuclear cells in an independent adult COVID-19 cohort (n = 42), comparing obese and nonobese subjects. Measurements and Main Results: Surprisingly, we found that obese adult subjects had attenuated lung immune or inflammatory responses in SARS-CoV-2 infection, with decreased expression of IFN-α, IFN-γ, and TNF-α (tumor necrosis factor α) response gene signatures in almost all lung epithelial and immune cell subsets, and lower expression of IFNG and TNF in specific lung immune cells. Peripheral blood immune cells in an independent adult cohort showed a similar but less marked reduction in type-I IFN and IFNγ response genes, as well as decreased serum IFNα, in obese patients with SARS-CoV-2. Nasal immune cells from obese children with COVID-19 also showed reduced enrichment of IFN-α and IFN-γ response genes. Conclusions: These findings show blunted tissue immune responses in obese patients with COVID-19, with implications for treatment stratification, supporting the specific application of inhaled recombinant type-I IFNs in this vulnerable subset.


Asunto(s)
COVID-19 , Interferón Tipo I , Obesidad Infantil , Adulto , Humanos , Niño , SARS-CoV-2 , Leucocitos Mononucleares , Pulmón/patología
3.
Proc Natl Acad Sci U S A ; 117(26): 15160-15171, 2020 06 30.
Artículo en Inglés | MEDLINE | ID: mdl-32541026

RESUMEN

IgG antibodies cause inflammation and organ damage in autoimmune diseases such as systemic lupus erythematosus (SLE). We investigated the metabolic profile of macrophages isolated from inflamed tissues in immune complex (IC)-associated diseases, including SLE and rheumatoid arthritis, and following IgG Fcγ receptor cross-linking. We found that human and mouse macrophages undergo a switch to glycolysis in response to IgG IC stimulation, mirroring macrophage metabolic changes in inflamed tissue in vivo. This metabolic reprogramming was required to generate a number of proinflammatory mediators, including IL-1ß, and was dependent on mTOR and hypoxia-inducible factor (HIF)1α. Inhibition of glycolysis, or genetic depletion of HIF1α, attenuated IgG IC-induced activation of macrophages in vitro, including primary human kidney macrophages. In vivo, glycolysis inhibition led to a reduction in kidney macrophage IL-1ß and reduced neutrophil recruitment in a murine model of antibody-mediated nephritis. Together, our data reveal the molecular mechanisms underpinning FcγR-mediated metabolic reprogramming in macrophages and suggest a therapeutic strategy for autoantibody-induced inflammation, including lupus nephritis.


Asunto(s)
Reprogramación Celular/fisiología , Nefritis Lúpica/metabolismo , Animales , Células Cultivadas , Dinoprostona/genética , Dinoprostona/metabolismo , Metabolismo Energético , Regulación de la Expresión Génica , Glucólisis/fisiología , Humanos , Inmunoglobulina G/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Riñón/citología , Macrófagos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Especies Reactivas de Oxígeno , Receptores de IgG/genética , Receptores de IgG/metabolismo
4.
J Immunol ; 205(5): 1376-1384, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32737150

RESUMEN

Acute kidney injury (AKI) is a serious condition affecting one fifth of hospital inpatients. B lymphocytes have immunological functions beyond Ab production and may produce cytokines and chemokines that modulate inflammation. In this study, we investigated leukocyte responses in a mouse model of AKI and observed an increase in circulating and kidney B cells, particularly a B220low subset, following AKI. We found that B cells produce the chemokine CCL7, with the potential to facilitate neutrophil and monocyte recruitment to the injured kidney. Siglec-G-deficient mice, which have increased numbers of B220low innate B cells and a lower B cell activation threshold, had increased Ccl7 transcripts, increased neutrophil and monocyte numbers in the kidney, and more severe AKI. CCL7 blockade in mice reduced myeloid cell infiltration into the kidney and ameliorated AKI. In two independent cohorts of human patients with AKI, we observed significantly higher CCL7 transcripts compared with controls, and in a third cohort, we observed an increase in urinary CCL7 levels in AKI, supporting the clinical importance of this pathway. Together, our data suggest that B cells contribute to early sterile inflammation in AKI via the production of leukocyte-recruiting chemokines.


Asunto(s)
Lesión Renal Aguda/inmunología , Linfocitos B/inmunología , Quimiocina CCL7/inmunología , Monocitos/inmunología , Neutrófilos/inmunología , Animales , Citocinas/inmunología , Modelos Animales de Enfermedad , Femenino , Humanos , Inflamación/inmunología , Riñón/inmunología , Leucocitos/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL
5.
J Am Chem Soc ; 141(15): 6122-6126, 2019 04 17.
Artículo en Inglés | MEDLINE | ID: mdl-30933483

RESUMEN

Iron oxide nanoparticles (IONPs) have emerging anticancer applications via polarizing tumor-associated macrophages from tumor-promoting phenotype (M2) to tumor-suppressing phenotype (M1). However, the underlying mechanism and structure-function relationship remain unclear. We report magnetite IONPs are more effective compared to hematite in M1 polarization and tumor suppression. Moreover, magnetite IONPs specifically rely on interferon regulatory factor 5 signaling pathway for M1 polarization and down-regulate M2-assoicated arginase-1. This study provides new understandings and paves the way for designing advanced iron-based anticancer technologies.


Asunto(s)
Compuestos Férricos/farmacología , Macrófagos/efectos de los fármacos , Nanopartículas/química , Transducción de Señal/efectos de los fármacos , Animales , Compuestos Férricos/química , Lipopolisacáridos/farmacología , Activación de Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Fenotipo , Células RAW 264.7
6.
Am J Physiol Endocrinol Metab ; 308(2): E159-71, 2015 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-25424999

RESUMEN

The Rar-related orphan receptor-α (Rorα) is a nuclear receptor that regulates adiposity and is a potential regulator of energy homeostasis. We have demonstrated that the Rorα-deficient staggerer (sg/sg) mice display a lean and obesity-resistant phenotype. Adaptive Ucp1-dependent thermogenesis in beige/brite and brown adipose tissue serves as a mechanism to increase energy expenditure and resist obesity. DEXA and MRI analysis demonstrated significantly decreased total fat mass and fat/lean mass tissue ratio in male chow-fed sg/sg mice relative to wt mice. In addition, we observed increased Ucp1 expression in brown adipose and subcutaneous white adipose tissue but not in visceral adipose tissue from Rorα-deficient mice. Moreover, this was associated with significant increases in the expression of the mRNAs encoding the thermogenic genes (i.e., markers of brown and beige adipose) Pparα, Errα, Dio2, Acot11/Bfit, Cpt1ß, and Cidea in the subcutaneous adipose in the sg/sg relative to WT mice. These changes in thermogenic gene expression involved the significantly increased expression of the (cell-fate controlling) histone-lysine N-methyltransferase 1 (Ehmt1), which stabilizes the Prdm16 transcriptional complex. Moreover, primary brown adipocytes from sg/sg mice displayed a higher metabolic rate, and further analysis was consistent with increased uncoupling. Finally, core body temperature analysis and infrared thermography demonstrated that the sg/sg mice maintained greater thermal control and cold tolerance relative to the WT littermates. We suggest that enhanced Ucp1 and thermogenic gene expression/activity may be an important contributor to the lean, obesity-resistant phenotype in Rorα-deficient mice.


Asunto(s)
Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Blanco/metabolismo , Regulación de la Expresión Génica/fisiología , Canales Iónicos/metabolismo , Proteínas Mitocondriales/metabolismo , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Obesidad/metabolismo , Termogénesis/fisiología , Absorciometría de Fotón , Animales , Composición Corporal/fisiología , Temperatura Corporal/fisiología , Proteínas de Unión al ADN/metabolismo , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Inmunohistoquímica , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Mutantes Neurológicos , Miembro 1 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , ARN/química , ARN/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Termogénesis/genética , Factores de Transcripción/metabolismo , Proteína Desacopladora 1
7.
Nat Commun ; 15(1): 682, 2024 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-38267413

RESUMEN

Tumour dendritic cells (DCs) internalise antigen and upregulate CCR7, which directs their migration to tumour-draining lymph nodes (dLN). CCR7 expression is coupled to an activation programme enriched in regulatory molecule expression, including PD-L1. However, the spatio-temporal dynamics of CCR7+ DCs in anti-tumour immune responses remain unclear. Here, we use photoconvertible mice to precisely track DC migration. We report that CCR7+ DCs are the dominant DC population that migrate to the dLN, but a subset remains tumour-resident despite CCR7 expression. These tumour-retained CCR7+ DCs are phenotypically and transcriptionally distinct from their dLN counterparts and heterogeneous. Moreover, they progressively downregulate the expression of antigen presentation and pro-inflammatory transcripts with more prolonged tumour dwell-time. Tumour-residing CCR7+ DCs co-localise with PD-1+CD8+ T cells in human and murine solid tumours, and following anti-PD-L1 treatment, upregulate stimulatory molecules including OX40L, thereby augmenting anti-tumour cytolytic activity. Altogether, these data uncover previously unappreciated heterogeneity in CCR7+ DCs that may underpin a variable capacity to support intratumoural cytotoxic T cells.


Asunto(s)
Linfocitos T CD8-positivos , Neoplasias , Humanos , Animales , Ratones , Receptores CCR7/genética , Neoplasias/genética , Neoplasias/terapia , Presentación de Antígeno , Células Dendríticas
8.
Nat Commun ; 15(1): 683, 2024 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-38267402

RESUMEN

Immune cell dysfunction within the tumor microenvironment (TME) undermines the control of cancer progression. Established tumors contain phenotypically distinct, tumor-specific natural killer (NK) cells; however, the temporal dynamics, mechanistic underpinning and functional significance of the NK cell compartment remains incompletely understood. Here, we use photo-labeling, combined with longitudinal transcriptomic and cellular analyses, to interrogate the fate of intratumoral NK cells. We reveal that NK cells rapidly lose effector functions and adopt a distinct phenotypic state with features associated with tissue residency. NK cell depletion from established tumors did not alter tumor growth, indicating that intratumoral NK cells cease to actively contribute to anti-tumor responses. IL-15 administration prevented loss of function and improved tumor control, generating intratumoral NK cells with both tissue-residency characteristics and enhanced effector function. Collectively, our data reveals the fate of NK cells after recruitment into tumors and provides insight into how their function may be revived.


Asunto(s)
Internado y Residencia , Neoplasias , Humanos , Perfilación de la Expresión Génica , Células Asesinas Naturales , Transcriptoma , Microambiente Tumoral
9.
Clin Transl Immunology ; 12(9): e1461, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37720629

RESUMEN

Objectives: Non-infectious uveitis is often secondary to systemic autoimmune diseases, with Behçet's disease (BD) and Vogt-Koyanagi-Harada disease (VKHD) as the two most common causes. Uveitis in BD and VKHD can show similar clinical manifestations, but the underlying immunopathogenesis remains unclear. Methods: To understand immune landscapes in inflammatory eye tissues, we performed single-cell RNA paired with T cell receptor (TCR) sequencing of immune cell infiltrates in aqueous humour from six patients with BD (N = 3) and VKHD (N = 3) uveitis patients. Results: Although T cells strongly infiltrated in both types of autoimmune uveitis, myeloid cells only significantly presented in BD uveitis but not in VKHD uveitis. Conversely, VKHD uveitis but not BD uveitis showed an overwhelming dominance by CD4+ T cells (> 80%) within the T cell population due to expansion of CD4+ T cell clusters with effector memory (Tem) phenotypes. Correspondingly, VKHD uveitis demonstrated a selective expansion of CD4+ T cell clones which were enriched in pro-inflammatory Granzyme H+ CD4+ Tem cluster and showed TCR and Th1 pathway activation. In contrast, BD uveitis showed a preferential expansion of CD8+ T cell clones in pro-inflammatory Granzyme H+ CD8+ Tem cluster, and pathway activation for cytoskeleton remodelling, cellular adhesion and cytotoxicity. Conclusion: Single-cell analyses of ocular tissues reveal distinct landscapes of immune cell infiltration and T-cell clonal expansions between VKHD and BD uveitis. Preferential involvements of pro-inflammatory CD4+ Th1 cells in VKHD and cytotoxic CD8+ T cells in BD suggest a difference in disease immunopathogenesis and can guide precision disease management.

10.
Nat Commun ; 14(1): 7081, 2023 11 04.
Artículo en Inglés | MEDLINE | ID: mdl-37925420

RESUMEN

B cells play a central role in humoral immunity but also have antibody-independent functions. Studies to date have focused on B cells in blood and secondary lymphoid organs but whether B cells reside in non-lymphoid organs (NLO) in homeostasis is unknown. Here we identify, using intravenous labeling and parabiosis, a bona-fide tissue-resident B cell population in lung, liver, kidney and urinary bladder, a substantial proportion of which are B-1a cells. Tissue-resident B cells are present in neonatal tissues and also in germ-free mice NLOs, albeit in lower numbers than in specific pathogen-free mice and following co-housing with 'pet-store' mice. They spatially co-localise with macrophages and regulate their polarization and function, promoting an anti-inflammatory phenotype, in-part via interleukin-10 production, with effects on bacterial clearance during urinary tract infection. Thus, our data reveal a critical role for tissue-resident B cells in determining the homeostatic 'inflammatory set-point' of myeloid cells, with important consequences for tissue immunity.


Asunto(s)
Linfocitos B , Macrófagos , Ratones , Animales , Anticuerpos , Hígado , Pulmón
11.
Biomater Adv ; 139: 213027, 2022 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-35882120

RESUMEN

The hematoma that forms between broken fragments of bone serves as a natural fibrin scaffold, and its removal from the defect site delays bone healing. The hypothesis of this study is that the microarchitectural and mechanical properties of the initially formed hematoma has a significant effect on the regulation of the biological process, which ultimately determines the outcome of bone healing. To mimic three healing conditions in the rat femur (normal, delayed, and non-healing bone defects), three different defect sizes of 0.5, 1.5, and 5.0 mm, are respectively used. The analysis of 3-day-old hematomas demonstrates clear differences in fibrin clot micro-architecture in terms of fiber diameter, fiber density, and porosity of the formed fibrin network, which result in different mechanical properties (stiffness) of the hematoma in each model. Those differences directly affect the biological processes involved. Specifically, RNA-sequencing reveals almost 700 differentially expressed genes between normally healing and non-healing defects, including significantly up-regulated essential osteogenic genes in normally healing defects, also differences in immune cell populations, activated osteogenic transcriptional regulators as well as potential novel marker genes. Most importantly, this study demonstrates that the healing outcome has already been determined during the hematoma phase of bone healing, three days post-surgery.


Asunto(s)
Curación de Fractura , Fracturas Óseas , Animales , Fibrina , Curación de Fractura/genética , Hematoma/genética , Osteogénesis/genética , Ratas
12.
JCI Insight ; 7(21)2022 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-36345939

RESUMEN

Lupus nephritis is a serious complication of systemic lupus erythematosus, mediated by IgG immune complex (IC) deposition in kidneys, with limited treatment options. Kidney macrophages are critical tissue sentinels that express IgG-binding Fcγ receptors (FcγRs), with previous studies identifying prenatally seeded resident macrophages as major IC responders. Using single-cell transcriptomic and spatial analyses in murine and human lupus nephritis, we sought to understand macrophage heterogeneity and subset-specific contributions in disease. In lupus nephritis, the cell fate trajectories of tissue-resident (TrMac) and monocyte-derived (MoMac) kidney macrophages were perturbed, with disease-associated transcriptional states indicating distinct pathogenic roles for TrMac and MoMac subsets. Lupus nephritis-associated MoMac subsets showed marked induction of FcγR response genes, avidly internalized circulating ICs, and presented IC-opsonized antigen. In contrast, lupus nephritis-associated TrMac subsets demonstrated limited IC uptake, but expressed monocyte chemoattractants, and their depletion attenuated monocyte recruitment to the kidney. TrMacs also produced B cell tissue niche factors, suggesting a role in supporting autoantibody-producing lymphoid aggregates. Extensive similarities were observed with human kidney macrophages, revealing cross-species transcriptional disruption in lupus nephritis. Overall, our study suggests a division of labor in the kidney macrophage response in lupus nephritis, with treatment implications - TrMacs orchestrate leukocyte recruitment while MoMacs take up and present IC antigen.


Asunto(s)
Lupus Eritematoso Sistémico , Nefritis Lúpica , Ratones , Humanos , Animales , Macrófagos , Monocitos/patología , Receptores de IgG/genética , Inmunoglobulina G
13.
J Exp Med ; 219(6)2022 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-35472220

RESUMEN

Improving the efficacy of immune checkpoint therapies will require a better understanding of how immune cells are recruited and sustained in tumors. Here, we used the photoconversion of the tumor immune cell compartment to identify newly entering lymphocytes, determine how they change over time, and investigate their egress from the tumor. Combining single-cell transcriptomics and flow cytometry, we found that while a diverse mix of CD8 T cell subsets enter the tumor, all CD8 T cells retained within this environment for more than 72 h developed an exhausted phenotype, revealing the rapid establishment of this program. Rather than forming tumor-resident populations, non-effector subsets, which express TCF-1 and include memory and stem-like cells, were continuously recruited into the tumor, but this recruitment was balanced by concurrent egress to the tumor-draining lymph node. Thus, the TCF-1+ CD8 T cell niche in tumors is highly dynamic, with the circulation of cells between the tumor and peripheral lymphoid tissue to bridge systemic and intratumoral responses.


Asunto(s)
Linfocitos T CD8-positivos , Neoplasias , Humanos , Inmunoterapia , Tejido Linfoide , Subgrupos de Linfocitos T
14.
Cell Rep ; 38(7): 110393, 2022 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-35143756

RESUMEN

B cells are important in immunity to both severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection and vaccination, but B cell receptor (BCR) repertoire development in these contexts has not been compared. We analyze serial samples from 171 SARS-CoV-2-infected individuals and 63 vaccine recipients and find the global BCR repertoire differs between them. Following infection, immunoglobulin (Ig)G1/3 and IgA1 BCRs increase, somatic hypermutation (SHM) decreases, and, in severe disease, IgM and IgA clones are expanded. In contrast, after vaccination, the proportion of IgD/M BCRs increase, SHM is unchanged, and expansion of IgG clones is prominent. VH1-24, which targets the N-terminal domain (NTD) and contributes to neutralization, is expanded post infection except in the most severe disease. Infection generates a broad distribution of SARS-CoV-2-specific clones predicted to target the spike protein, while a more focused response after vaccination mainly targets the spike's receptor-binding domain. Thus, the nature of SARS-CoV-2 exposure differentially affects BCR repertoire development, potentially informing vaccine strategies.


Asunto(s)
COVID-19/inmunología , Receptores de Antígenos de Linfocitos B/inmunología , Vacunación , Linfocitos B/inmunología , Vacuna BNT162/inmunología , COVID-19/prevención & control , Evolución Clonal , Humanos , Cadenas Pesadas de Inmunoglobulina/genética , Cadenas Pesadas de Inmunoglobulina/inmunología , Isotipos de Inmunoglobulinas/genética , Isotipos de Inmunoglobulinas/inmunología , Región Variable de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/inmunología , Cinética , Receptores de Antígenos de Linfocitos B/genética , SARS-CoV-2/inmunología , Índice de Severidad de la Enfermedad , Hipermutación Somática de Inmunoglobulina/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología
15.
J Exp Med ; 219(6)2022 06 06.
Artículo en Inglés | MEDLINE | ID: mdl-35551368

RESUMEN

Inborn errors of immunity (IEIs) unveil regulatory pathways of human immunity. We describe a new IEI caused by mutations in the GTPase of the immune-associated protein 6 (GIMAP6) gene in patients with infections, lymphoproliferation, autoimmunity, and multiorgan vasculitis. Patients and Gimap6-/- mice show defects in autophagy, redox regulation, and polyunsaturated fatty acid (PUFA)-containing lipids. We find that GIMAP6 complexes with GABARAPL2 and GIMAP7 to regulate GTPase activity. Also, GIMAP6 is induced by IFN-γ and plays a critical role in antibacterial immunity. Finally, we observed that Gimap6-/- mice died prematurely from microangiopathic glomerulosclerosis most likely due to GIMAP6 deficiency in kidney endothelial cells.


Asunto(s)
GTP Fosfohidrolasas , Síndromes de Inmunodeficiencia , Animales , Autofagia , Células Endoteliales/metabolismo , GTP Fosfohidrolasas/genética , GTP Fosfohidrolasas/metabolismo , Humanos , Inflamación , Ratones
16.
Nat Med ; 28(4): 766-779, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35190725

RESUMEN

B cells, which are critical for intestinal homeostasis, remain understudied in ulcerative colitis (UC). In this study, we recruited three cohorts of patients with UC (primary cohort, n = 145; validation cohort 1, n = 664; and validation cohort 2, n = 143) to comprehensively define the landscape of B cells during UC-associated intestinal inflammation. Using single-cell RNA sequencing, single-cell IgH gene sequencing and protein-level validation, we mapped the compositional, transcriptional and clonotypic landscape of mucosal and circulating B cells. We found major perturbations within the mucosal B cell compartment, including an expansion of naive B cells and IgG+ plasma cells with curtailed diversity and maturation. Furthermore, we isolated an auto-reactive plasma cell clone targeting integrin αvß6 from inflamed UC intestines. We also identified a subset of intestinal CXCL13-expressing TFH-like T peripheral helper cells that were associated with the pathogenic B cell response. Finally, across all three cohorts, we confirmed that changes in intestinal humoral immunity are reflected in circulation by the expansion of gut-homing plasmablasts that correlates with disease activity and predicts disease complications. Our data demonstrate a highly dysregulated B cell response in UC and highlight a potential role of B cells in disease pathogenesis.


Asunto(s)
Colitis Ulcerosa , Células Plasmáticas , Linfocitos B , Colitis Ulcerosa/genética , Humanos , Mucosa Intestinal/patología , Recuento de Linfocitos , Linfocitos T Colaboradores-Inductores
17.
Cancers (Basel) ; 13(9)2021 Apr 28.
Artículo en Inglés | MEDLINE | ID: mdl-33925140

RESUMEN

Ultraviolet (UV) radiation-induced tumours carry a high mutational load, are highly immunogenic, and often fail to grow when transplanted into normal, syngeneic mice. The aim of this study was to investigate factors critical for the immune-mediated rejection of cutaneous squamous cell carcinoma (SCC). In our rejection model, transplanted SCC establish and grow in mice immunosuppressed with tacrolimus. When tacrolimus is withdrawn, established SCC tumours subsequently undergo immune-mediated tumour rejection. Through the depletion of individual immune subsets at the time of tacrolimus withdrawal, we established a critical role for CD8+ T cells, but not CD4+ T cells, γδ T cells, or NK cells, in driving the regression of SCC. Regression was critically dependent on IFN-γ, although IFN-γ was not directly cytotoxic to SCC cells. IFN-γ-neutralisation abrogated SCC regression, significantly reduced CD8+ T cell-infiltration into SCC, and significantly impaired the secretion of CXCL9, CXCL10 and CCL5 within the tumour microenvironment. A strong positive correlation was revealed between CXCL10 expression and CD8+ T cell abundance in tumours. Indeed, blockade of the CXCL10 receptor CXCR3 at the time of tacrolimus withdrawal prevented CD8+ T cell infiltration and the regression of SCC. Chimeric models revealed an important role for immune cells as producers of IFN-γ, but not as recipients of IFN-γ signals via the IFN-γ receptor. Together, these findings suggest a key role for IFN-γ in driving the expression of chemokines within the tumour environment essential for the destruction of established SCC by CD8+ T cells.

18.
Front Microbiol ; 12: 789042, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-35145494

RESUMEN

Squamous cell carcinoma (SCC) is a common type of skin cancer that typically arises from premalignant precursor lesions named actinic keratoses (AK). Chronic inflammation is a well-known promoter of skin cancer progression. AK and SCC have been associated with an overabundance of the bacterium Staphylococcus aureus (S. aureus). Certain secreted products from S. aureus are known to promote cutaneous pro-inflammatory responses; however, not all S. aureus strains produce these. As inflammation plays a key role in SCC development, we investigated the pro-inflammatory potential and toxin secretion profiles of skin-cancer associated S. aureus. Sterile culture supernatants ("secretomes") of S. aureus clinical strains isolated from AK and SCC were applied to human keratinocytes in vitro. Some S. aureus secretomes induced keratinocytes to overexpress inflammatory mediators that have been linked to skin carcinogenesis, including IL-6, IL-8, and TNFα. A large phenotypic variation between the tested clinical strains was observed. Strains that are highly pro-inflammatory in vitro also caused more pronounced skin inflammation in mice. Proteomic characterization of S. aureus secretomes using mass spectrometry established that specific S. aureus enzymes and cytolytic toxins, including hemolysins, phenol-soluble modulins, and serine proteases, as well as currently uncharacterized proteins, correlate with the pro-inflammatory S. aureus phenotype. This study is the first to describe the toxin secretion profiles of AK and SCC-associated S. aureus, and their potential to induce a pro-inflammatory environment in the skin. Further studies are needed to establish whether these S. aureus products promote SCC development by mediating chronic inflammation.

19.
iScience ; 24(11): 103326, 2021 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-34805788

RESUMEN

Langerhans cells (LC) are skin-resident antigen-presenting cells that regulate immune responses to epithelial microorganisms. Human papillomavirus (HPV) infection can promote malignant epithelial transformation. As LCs are considered important for controlling HPV infection, we compared the transcriptome of murine LCs from skin transformed by K14E7 oncoprotein and from healthy skin. We identified transcriptome heterogeneity at the single cell level amongst LCs in normal skin, associated with ontogeny, cell cycle, and maturation. We identified a balanced co-existence of immune-stimulatory and immune-inhibitory LC cell states in normal skin that was significantly disturbed in HPV16 E7-transformed skin. Hyperplastic skin was depleted of immune-stimulatory LCs and enriched for LCs with an immune-inhibitory gene signature, and LC-keratinocyte crosstalk was dysregulated. We identified reduced expression of interleukin (IL)-34, a critical molecule for LC homeostasis. Enrichment of an immune-inhibitory LC gene signature and reduced levels of epithelial IL-34 were also found in human HPV-associated cervical epithelial cancers.

20.
Cell Rep ; 32(1): 107857, 2020 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-32640223

RESUMEN

Macrophages play a central role in intestinal immunity, but inappropriate macrophage activation is associated with inflammatory bowel disease (IBD). Here, we identify granulocyte-macrophage colony stimulating factor (GM-CSF) as a critical regulator of intestinal macrophage activation in patients with IBD and mice with dextran sodium sulfate (DSS)-induced colitis. We find that GM-CSF drives the maturation and polarization of inflammatory intestinal macrophages, promoting anti-microbial functions while suppressing wound-healing transcriptional programs. Group 3 innate lymphoid cells (ILC3s) are a major source of GM-CSF in intestinal inflammation, with a strong positive correlation observed between ILC or CSF2 transcripts and M1 macrophage signatures in IBD mucosal biopsies. Furthermore, GM-CSF-dependent macrophage polarization results in a positive feedback loop that augmented ILC3 activation and type 17 immunity. Together, our data reveal an important role for GM-CSF-mediated ILC-macrophage crosstalk in calibrating intestinal macrophage phenotype to enhance anti-bacterial responses, while inhibiting pro-repair functions associated with fibrosis and stricturing, with important clinical implications.


Asunto(s)
Infecciones por Enterobacteriaceae/patología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Inflamación/patología , Intestinos/patología , Macrófagos/patología , Cicatrización de Heridas , Animales , Polaridad Celular , Citrobacter rodentium/fisiología , Colitis/complicaciones , Colitis/inmunología , Colitis/patología , Humanos , Inmunidad Innata , Linfocitos/inmunología , Activación de Macrófagos , Ratones Endogámicos C57BL , Fenotipo
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