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1.
Front Immunol ; 13: 973991, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36081511

RESUMO

Impaired immune responses have been observed in patients with type-2 diabetes mellitus (T2DM), which increases susceptibility to tuberculosis infection. However, the effect of the tuberculosis infection on the immunological and metabolic features of T2DM is largely unknown. To investigate this question, age- and sex-matched patients with pulmonary tuberculosis (PTB), T2DM, or T2DM combined with PTB were recruited from the Infectious Disease Hospital of Heilongjiang Province between January and September 2020. Healthy subjects were used as controls. Cytokines and chemokines in fasting serum samples were determined using the Quantibody Inflammation Array. Compared with T2DM alone, patients with T2DM combined with PTB have higher fasting blood glucose levels and monocyte counts in circulation. Among the four groups, circulating IL-10 levels peaked in patients with T2DM and PTB (p<0.05). Univariate linear analysis showed that serum IL-10 levels were positively associated with myeloid cells but negatively correlated with lymphocyte counts in these patients (p<0.05). Serum IL-6 levels were 1.6-fold higher in patients with T2DM plus PTB than in those with T2DM alone. In conclusion, PTB infection in patients with T2DM had distinct inflammatory profiles and sustained hyperglycaemia compared with PTB or T2DM alone. IL-10 levels and elevated monocyte counts could be hallmarks of patients with T2DM infected with PTB.


Assuntos
Diabetes Mellitus Tipo 2 , Tuberculose Pulmonar , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Interleucina-10 , Tuberculose Latente , Tuberculose , Tuberculose Pulmonar/complicações
2.
J Biol Chem ; 298(9): 102312, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35921894

RESUMO

Cytokine-induced beta cell dysfunction is a hallmark of type 2 diabetes (T2D). Chronic exposure of beta cells to inflammatory cytokines affects gene expression and impairs insulin secretion. Thus, identification of anti-inflammatory factors that preserve beta cell function represents an opportunity to prevent or treat T2D. Butyrate is a gut microbial metabolite with anti-inflammatory properties for which we recently showed a role in preventing interleukin-1ß (IL-1ß)-induced beta cell dysfunction, but how prevention is accomplished is unclear. Here, we investigated the mechanisms by which butyrate exerts anti-inflammatory activity in beta cells. We exposed mouse islets and INS-1E cells to a low dose of IL-1ß and/or butyrate and measured expression of inflammatory genes and nitric oxide (NO) production. Additionally, we explored the molecular mechanisms underlying butyrate activity by dissecting the activation of the nuclear factor-κB (NF-κB) pathway. We found that butyrate suppressed IL-1ß-induced expression of inflammatory genes, such as Nos2, Cxcl1, and Ptgs2, and reduced NO production. Butyrate did not inhibit IκBα degradation nor NF-κB p65 nuclear translocation. Furthermore, butyrate did not affect binding of NF-κB p65 to target sequences in synthetic DNA but inhibited NF-κB p65 binding and RNA polymerase II recruitment to inflammatory gene promoters in the context of native DNA. We found this was concurrent with increased acetylation of NF-κB p65 and histone H4, suggesting butyrate affects NF-κB activity via inhibition of histone deacetylases. Together, our results show butyrate inhibits IL-1ß-induced inflammatory gene expression and NO production through suppression of NF-κB activation and thereby possibly preserves beta cell function.


Assuntos
Anti-Inflamatórios não Esteroides , Butiratos , Diabetes Mellitus Tipo 2 , Inibidores de Histona Desacetilases , Inflamação , Células Secretoras de Insulina , Interleucina-1beta , NF-kappa B , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Butiratos/farmacologia , Ciclo-Oxigenase 2/metabolismo , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/patologia , Regulação da Expressão Gênica , Inibidores de Histona Desacetilases/farmacologia , Histona Desacetilases/metabolismo , Histonas/metabolismo , Inflamação/genética , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/metabolismo , Interleucina-1beta/antagonistas & inibidores , Interleucina-1beta/metabolismo , Interleucina-1beta/farmacologia , Camundongos , Inibidor de NF-kappaB alfa/metabolismo , NF-kappa B/metabolismo , Óxido Nítrico/biossíntese , RNA Polimerase II/metabolismo
3.
Front Immunol ; 13: 814203, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35145521

RESUMO

T cells and B cells have been identified in human and murine islets, but the phenotype and role of islet lymphocytes is unknown. Resident immune populations set the stage for responses to inflammation in the islets during homeostasis and diabetes. Thus, we sought to identify the phenotype and effector function of islet lymphocytes to better understand their role in normal islets and in islets under metabolic stress. Lymphocytes were located in the islet parenchyma, and were comprised of a mix of naïve, activated, and memory T cell and B cell subsets, with an enrichment for regulatory B cell subsets. Use of a Nur77 reporter indicated that CD8 T cells and B cells both received local antigen stimulus, indicating that they responded to antigens present in the islets. Analysis of effector function showed that islet T cells and B cells produced the regulatory cytokine IL-10. The regulatory phenotype of islet T cells and B cells and their response to local antigenic stimuli remained stable under conditions of metabolic stress in the diet induced obesity (DIO) model. T cells present in human islets retained a similar activated and memory phenotype in non-diabetic and T2D donors. Under steady-state conditions, islet T cells and B cells have a regulatory phenotype, and thus may play a protective role in maintaining tissue homeostasis.


Assuntos
Linfócitos B Reguladores/imunologia , Homeostase/fisiologia , Ilhotas Pancreáticas/imunologia , Estresse Fisiológico/fisiologia , Linfócitos T/imunologia , Animais , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 2/imunologia , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Obesidade/imunologia , Fenótipo
4.
Diabetes Metab Syndr ; 16(2): 102406, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-35104750

RESUMO

BACKGROUND AND AIM: DM patients' antibody response after the COVID-19 vaccine is still unknown amid the COVID-19 vaccination rollout. This study aimed to explore the SARS-CoV-2 antibody response or seropositivity among DM patients following the COVID-19 vaccine administration. METHODS: We performed a systematic review of the literature consisting of observational or cross-sectional studies, which reported the antibody serology or seropositivity among DM patients by following the PRISMA 2020 guidelines. RESULTS: Eight studies with a total of 64468 patients were identified, and 5156 (7.9%) of them had diabetes. Most studies showed that antibody response and seropositivity in DM patients were lower than healthy population after one until four weeks following full COVID-19 vaccination dose. CONCLUSION: The antibody response and seropositivity after the COVID-19 vaccine in DM patients were lower than in healthy subjects. Therefore, DM patients are expected to receive vaccines according to the dose and schedule appropriately and might be prioritized to receive vaccine boosters.


Assuntos
Formação de Anticorpos/imunologia , Vacinas contra COVID-19/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Diabetes Mellitus Tipo 2/imunologia , SARS-CoV-2/imunologia , Anticorpos Antivirais/sangue , COVID-19/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Vacinação
5.
Biomed Res Int ; 2022: 9920744, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35187175

RESUMO

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by chronic low-grade inflammation, showing an increasing trend. The infiltration of immune cells into adipose tissue has been shown to be an important pathogenic cause of T2DM. The purpose of this study is to use the relevant database to identify some abnormally expressed or dysfunctional genes related to diabetes from the perspective of immune infiltration. METHODS: Weighted gene coexpression network analysis (WGCNA) was employed to systematically identify the coexpressed gene modules and hub genes associated with T2DM development based on a microarray dataset (GSE23561) from the Gene Expression Omnibus (GEO) database. The key genes in modules highly related to clinical features were calculated and screened by using R software, and their participation in T2DM was determined by gene enrichment analysis. The mRNA levels of CSF1R, H2AFV, LCK, and TLR9 in pre-T2DM mice and normal wild-type mice were detected by WGCNA screening and real-time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). RESULTS: We constructed 14 coexpressed gene modules, and the brown module was shown to be significantly related to T2DM. Through verification of the protein-protein interaction (PPI) network, four upregulated hub genes, CSF1R, H2AFV, LCK, and TLR9, were screened from the brown module and successfully distinguishedT2DM patients from healthy people. These hub genes may be used as biomarkers and important indicators for patient diagnosis. Enrichment analysis showed that these hub genes were highly associated with IL-6-related inflammatory metabolism, immune regulation, and immune cell infiltration. Finally, we verified the hub genes CSF1R, LCK, and TLR9 in a T2DM animal model and found that their mRNA levels were significantly higher in animals with T2DM than in control group mice (NC). CONCLUSIONS: In summary, our results suggest that these hub genes (CSF1R, LCK, and TLR9) can serve as biomarkers and immunotherapeutic targets for T2DM.


Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Proteínas Adaptadoras de Transdução de Sinal/genética , Animais , Biomarcadores , Bases de Dados Genéticas , Dieta Hiperlipídica , Histonas/genética , Camundongos , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptor Toll-Like 9/genética
6.
Gut Microbes ; 14(1): 2031696, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35130127

RESUMO

Obesity and type 2 diabetes (T2D) are growing burdens for individuals and the health-care system. Bariatric surgery is an efficient, but drastic treatment to reduce body weight, normalize glucose values, and reduce low-grade inflammation. The gut microbiome, which is in part controlled by intestinal antibodies, such as IgA, is involved in the development of both conditions. Knowledge of the effect of bariatric surgery on systemic and intestinal antibody response is limited. Here, we determined the fecal antibody and gut microbiome response in 40 T2D and non-diabetic (ND) obese individuals that underwent bariatric surgery (N = 40). Body weight, fasting glucose concentrations and inflammatory parameters decreased after bariatric surgery, whereas pro-inflammatory bacterial species such as lipopolysaccharide (LPS), and flagellin increased in the feces. Simultaneously, concentrations of LPS- and flagellin-specific intestinal IgA levels increased with the majority of pro-inflammatory bacteria coated with IgA after surgery. Finally, serum antibodies decreased in both groups, along with a lower inflammatory tone. We conclude that intestinal rearrangement by bariatric surgery leads to expansion of typical pro-inflammatory bacteria, which may be compensated by an improved antibody response. Although further evidence and mechanistic insights are needed, we postulate that this apparent compensatory antibody response might help to reduce systemic inflammation by neutralizing intestinal immunogenic components and thereby enhance intestinal barrier function after bariatric surgery.


Assuntos
Anticorpos Antibacterianos/sangue , Bactérias/imunologia , Diabetes Mellitus Tipo 2/imunologia , Microbioma Gastrointestinal , Intestinos/microbiologia , Obesidade/imunologia , Anticorpos Antibacterianos/imunologia , Bactérias/classificação , Bactérias/genética , Bactérias/isolamento & purificação , Cirurgia Bariátrica , Estudos de Coortes , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/microbiologia , Diabetes Mellitus Tipo 2/cirurgia , Fezes/química , Fezes/microbiologia , Humanos , Imunoglobulina A/sangue , Imunoglobulina A/imunologia , Intestinos/imunologia , Obesidade/sangue , Obesidade/microbiologia , Obesidade/cirurgia
7.
J Diabetes Res ; 2022: 2552186, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35036446

RESUMO

BACKGROUND: Previous studies have revealed that the variation of thyroid indicators may be associated with the risk of diabetic retinopathy (DR) among euthyroid type 2 diabetes (T2D) patients. But the specific conclusions are currently inconsistent. METHODS: This is a hospital-based retrospective survey. We recruited 1,145 euthyroid T2D patients and checked the thyroid function and fundus photographs. The modified Airlie House classification system was used to categorize the stages of DR. The association between thyroid indicators and different stages of DR was analyzed. RESULTS: We divided free triiodothyronine (FT3) into tertiles and found that the prevalence of mild nonproliferative DR (NPDR) was significantly higher in T2, compared with T1 (32.0% vs. 25.2%, p < 0.05). When FT3 was within the level of T2, FT3 could be an independent risk factor for mild NPDR (OR 1.426, 95% CI (1.031, 1.971), p < 0.05). In addition, the prevalence of severe NPDR and proliferative DR (PDR) was significantly higher in thyroglobulin antibody (TgAb) positive group (8.8% vs. 4.1%, p < 0.05) and vice versa (33.3% vs. 18.4%, p < 0.05). TgAb positivity was also an independent risk factor for severe NPDR and PDR (OR 2.212, 95% CI (1.244, 3.934), p < 0.05). CONCLUSIONS: We hardly observed a significant change in DR risk with the elevation or reduction of serum TSH or thyroid hormone within the reference interval. Although the slightly elevated FT3 may be associated to mild NPDR, the extensibility of this result remains to be seen. For T2D patients with euthyroid function, there may be a significant correlation between serum TgAb positivity and severe NPDR and PDR.


Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 2/imunologia , Retinopatia Diabética/imunologia , Tireoglobulina/imunologia , Adulto , Idoso , Diabetes Mellitus Tipo 2/sangue , Retinopatia Diabética/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Testes de Função Tireóidea
8.
Diabetes ; 71(3): 497-510, 2022 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35040477

RESUMO

Colorectal cancer (CRC) and diabetes are two of the most prevalent chronic diseases worldwide with dysregulated receptor tyrosine kinase signaling and strong co-occurrence correlation. Plasma autoantibodies represent a promising early diagnostic marker for both diseases before symptoms appear. In this study, we explore the value of autoantibodies against receptor-type tyrosine-protein phosphatase-like N (PTPRN; full-length or selected domains) as diagnostic markers using a cohort of individuals with type 2 diabetes (T2D), CRC, or both diseases or healthy individuals. We show that PTPRN autoantibody levels in plasma discriminated between patients with T2D with and without CRC. Consistently, high PTPRN expression correlated with decreased survival of patients with CRC. Mechanistically, PTPRN depletion significantly reduced invasiveness of CRC cells in vitro and liver homing and metastasis in vivo by means of a dysregulation of the epithelial-mesenchymal transition and a decrease of the insulin receptor signaling pathway. Therefore, PTPRN autoantibodies may represent a particularly helpful marker for the stratification of patients with T2D at high risk of developing CRC. Consistent with the critical role played by tyrosine kinases in diabetes and tumor biology, we provide evidence that tyrosine phosphatases such as PTPRN may hold potential as therapeutic targets in patients with CRC.


Assuntos
Autoanticorpos/sangue , Neoplasias Colorretais/imunologia , Diabetes Mellitus Tipo 2/imunologia , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/imunologia , Proteínas Tirosina Fosfatases Classe 8 Semelhantes a Receptores/fisiologia , Adulto , Animais , Biomarcadores/sangue , Linhagem Celular Tumoral , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais/mortalidade , Feminino , Humanos , Neoplasias Hepáticas/secundário , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Transplante de Neoplasias , Fatores de Risco
9.
Immunity ; 55(1): 31-55, 2022 01 11.
Artigo em Inglês | MEDLINE | ID: mdl-35021057

RESUMO

Obesity leads to chronic, systemic inflammation and can lead to insulin resistance (IR), ß-cell dysfunction, and ultimately type 2 diabetes (T2D). This chronic inflammatory state contributes to long-term complications of diabetes, including non-alcoholic fatty liver disease (NAFLD), retinopathy, cardiovascular disease, and nephropathy, and may underlie the association of type 2 diabetes with other conditions such as Alzheimer's disease, polycystic ovarian syndrome, gout, and rheumatoid arthritis. Here, we review the current understanding of the mechanisms underlying inflammation in obesity, T2D, and related disorders. We discuss how chronic tissue inflammation results in IR, impaired insulin secretion, glucose intolerance, and T2D and review the effect of inflammation on diabetic complications and on the relationship between T2D and other pathologies. In this context, we discuss current therapeutic options for the treatment of metabolic disease, advances in the clinic and the potential of immune-modulatory approaches.


Assuntos
Complicações do Diabetes/imunologia , Diabetes Mellitus Tipo 2/imunologia , Inflamação/imunologia , Obesidade/imunologia , Animais , Humanos , Imunomodulação , Resistência à Insulina
10.
J Mol Med (Berl) ; 100(1): 101-113, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34651203

RESUMO

Infections are common in patients with diabetes, but increasing antibiotic resistance hampers successful bacterial clearance and calls for alternative treatment strategies. Hypoxia-inducible factor 1 (HIF-1) is known to influence the innate immune defense and could therefore serve as a possible target. However, the impact of high glucose on HIF-1 has received little attention and merits closer investigation. Here, we show that higher levels of proinflammatory cytokines and CAMP, encoding for the antimicrobial peptide cathelicidin, LL-37, correlate with HIF-1 in type 2 diabetic patients. Chemical activation of HIF-1 further enhanced LL-37, IL-1ß, and IL-8 in human uroepithelial cells exposed to high glucose. Moreover, HIF-1 activation of transurethrally infected diabetic mice resulted in lower bacterial load. Drugs activating HIF-1 could therefore in the future potentially have a therapeutic role in clearing bacteria in diabetic patients with infections where antibiotic treatment failed. KEY MESSAGES: • Mohanty et al. "HIF-1 mediated activation of antimicrobial peptide LL-37 in type 2 diabetic patients." • Our study highlights induction of the antimicrobial peptide, LL-37, and strengthening of the innate immunity through hypoxia-inducible factor 1 (HIF-1) in diabetes. • Our key observations are: 1. HIF-1 activation increased LL-37 expression in human urothelial cells treated with high glucose. In line with that, we demonstrated that patients with type 2 diabetes living at high altitude had increased levels of the LL-37. 2. HIF-1 activation increased IL-1ß and IL-8 in human uroepithelial cells treated with high glucose concentration. 3. Pharmacological activation of HIF-1 decreased bacterial load in the urinary bladder of mice with hereditary diabetes. • We conclude that enhancing HIF-1 may along with antibiotics in the future contribute to the treatment in selected patient groups where traditional therapy is not possible.


Assuntos
Peptídeos Catiônicos Antimicrobianos/imunologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 2/imunologia , Infecções por Escherichia coli/imunologia , Fator 1 Induzível por Hipóxia/imunologia , Infecções Urinárias/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Citocinas/genética , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Tipo 2/genética , Infecções por Escherichia coli/genética , Feminino , Humanos , Fator 1 Induzível por Hipóxia/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Infecções Urinárias/genética , Urotélio/citologia
11.
Diabetes ; 71(2): 264-274, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-34737186

RESUMO

A disparate array of plasma/serum markers provides evidence for chronic inflammation in human prediabetes, a condition that is most closely replicated by standard mouse models of obesity and metaflammation. These remain largely nonactionable and contrast with our rich understanding of inflammation in human type 2 diabetes. New data show that inflammatory profiles produced by CD4+ T cells define human prediabetes as a unique inflammatory state. Regulatory T cells (Treg) control mitochondrial function and cytokine production by CD4+ effector T cells (Teff) in prediabetes and type 2 diabetes by supporting T helper (Th)17 or Th1 cytokine production, respectively. These data suggest that Treg control of Teff metabolism regulates inflammation differentially in prediabetes compared with type 2 diabetes. Queries of genes that impact mitochondrial function or pathways leading to transcription of lipid metabolism genes identified the fatty acid importer CD36 as highly expressed in Treg but not Teff from subjects with prediabetes. Pharmacological blockade of CD36 in Treg from subjects with prediabetes decreased Teff production of the Th17 cytokines that differentiate overall prediabetes inflammation. We conclude that Treg control CD4+ T cell cytokine profiles through mechanisms determined, at least in part, by host metabolic status. Furthermore, Treg CD36 uniquely promotes Th17 cytokine production by Teff in prediabetes.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Inflamação/imunologia , Estado Pré-Diabético/imunologia , Linfócitos T Reguladores/fisiologia , Linfócitos T CD4-Positivos/patologia , Células Cultivadas , Estudos de Coortes , Citocinas/metabolismo , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/metabolismo , Humanos , Inflamação/genética , Inflamação/metabolismo , Obesidade/complicações , Obesidade/genética , Obesidade/imunologia , Obesidade/metabolismo , Estado Pré-Diabético/metabolismo , Células Th17/metabolismo , Transcriptoma/imunologia
12.
FASEB J ; 36(1): e22107, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34939700

RESUMO

Mounting evidence has linked the metabolic disease to neurovascular disorders and cognitive decline. Using a murine model of a high-fat high-sugar diet mimicking obesity-induced type 2 diabetes mellitus (T2DM) in humans, we show that pro-inflammatory mediators and altered immune responses damage the blood-brain barrier (BBB) structure, triggering a proinflammatory metabolic phenotype. We find that disruption to tight junctions and basal lamina due to loss of control in the production of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) causes BBB impairment. Together the disruption to the structural and functional integrity of the BBB results in enhanced transmigration of leukocytes across the BBB that could contribute to an initiation of a neuroinflammatory response through activation of microglia. Using a humanized in vitro model of the BBB and T2DM patient post-mortem brains, we show the translatable applicability of our results. We find a leaky BBB phenotype in T2DM patients can be attributed to a loss of junctional proteins through changes in inflammatory mediators and MMP/TIMP levels, resulting in increased leukocyte extravasation into the brain parenchyma. We further investigated therapeutic avenues to reduce and restore the BBB damage caused by HFHS-feeding. Pharmacological treatment with recombinant annexin A1 (hrANXA1) or reversion from a high-fat high-sugar diet to a control chow diet (dietary intervention), attenuated T2DM development, reduced inflammation, and restored BBB integrity in the animals. Given the rising incidence of diabetes worldwide, understanding metabolic-disease-associated brain microvessel damage is vital and the proposed therapeutic avenues could help alleviate the burden of these diseases.


Assuntos
Barreira Hematoencefálica/imunologia , Colagenases/imunologia , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 2/imunologia , Inibidores Teciduais de Metaloproteinases/imunologia , Animais , Anexina A1/farmacologia , Barreira Hematoencefálica/patologia , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/patologia , Humanos , Masculino , Camundongos , Proteínas Recombinantes/farmacologia
13.
Signal Transduct Target Ther ; 6(1): 409, 2021 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-34848693

RESUMO

Natural killer (NK) cells have been suggested to be associated with type 2 diabetes by regulating systemic inflammation. However, the mechanism by which NK cells regulate insulin sensitivity remains unknown. This study shows that NK-derived exosomes from lean mice attenuate obesity-induced insulin resistance and inflammation in mice of type 2 diabetes. Moreover, lean NK-derived exosomes enhance insulin sensitivity and relieve inflammation in adipocytes and hepatocytes. MiR-1249-3p, which is significantly upregulated in lean NK-derived exosomes, can be transferred from NK cells to adipocytes and hepatocytes via exosomes. NK-derived exosomal miR-1249-3p dramatically induces cellular insulin sensitivity and relieves inflammation. Mechanistically, exosomal miR-1249-3p directly targets SKOR1 to regulate the formation of ternary complex SMAD6/MYD88/SMURF1, which mediates glucose homeostasis by suppressing the TLR4/NF-κB signaling pathway. This study reveals an emerging role for NK-derived exosomal miR-1249-3p in remission of insulin resistance, and provides a series of potential therapeutic targets in type 2 diabetes.


Assuntos
Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 2/imunologia , Exossomos/imunologia , Resistência à Insulina/imunologia , Células Matadoras Naturais/imunologia , MicroRNAs/imunologia , Animais , Inflamação/imunologia , Masculino , Camundongos
14.
Biomolecules ; 11(12)2021 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-34944407

RESUMO

Type 2 diabetes is an established risk factor for tuberculosis, but the underlying mechanisms are largely unknown. We established an in vitro model to analyze the effect of high glucose concentrations in antigen processing and presentation in antigen-presenting cells. Human monocyte-derived macrophages (MDMs) were exposed to high (11 mM and 30 mM) and low (5.5 mM) glucose concentrations and infected with Mycobacterium tuberculosis (Mtb). Flow cytometry was used to analyze the effect of high glucose concentrations in histocompatibility complex (MHC) class II molecules (HLA-DR) and co-stimulatory molecules (CD80 and CD86), indispensable for an adequate antigenic presentation and CD4+ T cell activation. HLA-DR and CD86 were significantly decreased by high glucose concentrations compared with low glucose concentrations. Confocal microscopy was used to detect Rab 5 and Lamp-1, proteins involved in the kinetics of antigen processing as early markers, and Rab 7 and cathepsin D as late markers. We observed a delay in the dynamics of the acquisition of Rab 7 and cathepsin D in high glucose concentrations. Moreover, the kinetics of the formation M. tuberculosis peptide-MHC II complexes in MDMs was decreased under high glucose concentrations, reducing their capacity for T cell activation. These findings suggest that high glucose concentrations directly affect antigenic processing, and therefore antigenic presentation.


Assuntos
Antígeno B7-2/metabolismo , Diabetes Mellitus Tipo 2/microbiologia , Glucose/efeitos adversos , Antígenos HLA-DR/metabolismo , Macrófagos/imunologia , Mycobacterium tuberculosis/imunologia , Apresentação de Antígeno/efeitos dos fármacos , Antígenos de Bactérias/metabolismo , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 2/imunologia , Regulação para Baixo , Citometria de Fluxo , Humanos , Macrófagos/microbiologia , Modelos Biológicos
15.
Front Immunol ; 12: 767359, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34966388

RESUMO

Melioidosis is a potentially fatal bacterial disease caused by Burkholderia pseudomallei and is estimated to cause 89,000 deaths per year in endemic areas of Southeast Asia and Northern Australia. People with diabetes mellitus are most at risk of melioidosis, with a 12-fold increased susceptibility for severe disease. Interferon gamma (IFN-γ) responses from CD4 and CD8 T cells, but also from natural killer (NK) and natural killer T (NKT) cells, are necessary to eliminate the pathogen. We previously reported that immunization with B. pseudomallei OmpW (BpOmpW antigen) protected mice from lethal B. pseudomallei challenge for up to 81 days. Elucidating the immune correlates of protection of the protective BpOmpW vaccine is an essential step prior to clinical trials. Thus, we immunized either non-insulin-resistant C57BL/6J mice or an insulin-resistant C57BL/6J mouse model of type 2 diabetes (T2D) with a single dose of BpOmpW. BpOmpW induced strong antibody responses, stimulated effector CD4+ and CD8+ T cells and CD4+ CD25+ Foxp3+ regulatory T cells, and produced higher IFN-γ responses in CD4+, CD8+, NK, and NKT cells in non-insulin-resistant mice. The T-cell responses of insulin-resistant mice to BpOmpW were comparable to those of non-insulin-resistant mice. In addition, as a precursor to its evaluation in human studies, humanized HLA-DR and HLA-DQ (human leukocyte antigen DR and DQ isotypes, respectively) transgenic mice elicited IFN-γ recall responses in an enzyme-linked immune absorbent spot (ELISpot)-based study. Moreover, human donor peripheral blood mononuclear cells (PBMCs) exposed to BpOmpW for 7 days showed T-cell proliferation. Finally, plasma from melioidosis survivors with diabetes recognized our BpOmpW vaccine antigen. Overall, the range of approaches used strongly indicated that BpOmpW elicits the necessary immune responses to combat melioidosis and bring this vaccine closer to clinical trials.


Assuntos
Antígenos de Bactérias/imunologia , Proteínas da Membrana Bacteriana Externa/imunologia , Vacinas Bacterianas/imunologia , Burkholderia pseudomallei/imunologia , Melioidose/imunologia , Linfócitos T/imunologia , Animais , Vacinas Bacterianas/administração & dosagem , Burkholderia pseudomallei/metabolismo , Burkholderia pseudomallei/fisiologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD4-Positivos/microbiologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linfócitos T CD8-Positivos/microbiologia , Células Cultivadas , Diabetes Mellitus Tipo 2/imunologia , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Células Matadoras Naturais/microbiologia , Masculino , Melioidose/microbiologia , Melioidose/prevenção & controle , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Linfócitos T/metabolismo , Linfócitos T/microbiologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/microbiologia
16.
Front Immunol ; 12: 752233, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34899701

RESUMO

The emergence of effective vaccines for COVID-19 has been welcomed by the world with great optimism. Given their increased susceptibility to COVID-19, the question arises whether individuals with type-2 diabetes mellitus (T2DM) and other metabolic conditions can respond effectively to the mRNA-based vaccine. We aimed to evaluate the levels of anti-SARS-CoV-2 IgG and neutralizing antibodies in people with T2DM and/or other metabolic risk factors (hypertension and obesity) compared to those without. This study included 262 people (81 diabetic and 181 non-diabetic persons) that took two doses of BNT162b2 (Pfizer-BioNTech) mRNA vaccine. Both T2DM and non-diabetic individuals had a robust response to vaccination as demonstrated by their high antibody titers. However, both SARS-CoV-2 IgG and neutralizing antibodies titers were lower in people with T2DM. The mean ( ± 1 standard deviation) levels were 154 ± 49.1 vs. 138 ± 59.4 BAU/ml for IgG and 87.1 ± 11.6 vs. 79.7 ± 19.5% for neutralizing antibodies in individuals without diabetes compared to those with T2DM, respectively. In a multiple linear regression adjusted for individual characteristics, comorbidities, previous COVID-19 infection, and duration since second vaccine dose, diabetics had 13.86 BAU/ml (95% CI: 27.08 to 0.64 BAU/ml, p=0.041) less IgG antibodies and 4.42% (95% CI: 8.53 to 0.32%, p=0.036) fewer neutralizing antibodies than non-diabetics. Hypertension and obesity did not show significant changes in antibody titers. Taken together, both type-2 diabetic and non-diabetic individuals elicited strong immune responses to SARS-CoV-2 BNT162b2 mRNA vaccine; nonetheless, lower levels were seen in people with diabetes. Continuous monitoring of the antibody levels might be a good indicator to guide personalized needs for further booster shots to maintain adaptive immunity. Nonetheless, it is important that people get their COVID-19 vaccination especially people with diabetes.


Assuntos
Anticorpos Neutralizantes/imunologia , Anticorpos Antivirais/imunologia , COVID-19/imunologia , Diabetes Mellitus Tipo 2/imunologia , SARS-CoV-2/imunologia , Imunidade Adaptativa/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Neutralizantes/sangue , Anticorpos Antivirais/sangue , COVID-19/prevenção & controle , COVID-19/virologia , Feminino , Humanos , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , SARS-CoV-2/genética , SARS-CoV-2/fisiologia , Vacinação , Adulto Jovem
17.
Front Immunol ; 12: 746151, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34804028

RESUMO

Diabetes mellitus type II and obesity are two important causes of death in modern society. They are characterized by low-grade chronic inflammation and metabolic dysfunction (meta-inflammation), which is observed in all tissues involved in energy homeostasis. A substantial body of evidence has established an important role for macrophages in these tissues during the development of diabetes mellitus type II and obesity. Macrophages can activate into specialized subsets by cues from their microenvironment to handle a variety of tasks. Many different subsets have been described and in diabetes/obesity literature two main classifications are widely used that are also defined by differential metabolic reprogramming taking place to fuel their main functions. Classically activated, pro-inflammatory macrophages (often referred to as M1) favor glycolysis, produce lactate instead of metabolizing pyruvate to acetyl-CoA, and have a tricarboxylic acid cycle that is interrupted at two points. Alternatively activated macrophages (often referred to as M2) mainly use beta-oxidation of fatty acids and oxidative phosphorylation to create energy-rich molecules such as ATP and are involved in tissue repair and downregulation of inflammation. Since diabetes type II and obesity are characterized by metabolic alterations at the organism level, these alterations may also induce changes in macrophage metabolism resulting in unique macrophage activation patterns in diabetes and obesity. This review describes the interactions between metabolic reprogramming of macrophages and conditions of metabolic dysfunction like diabetes and obesity. We also focus on different possibilities of measuring a range of metabolites intra-and extracellularly in a precise and comprehensive manner to better identify the subsets of polarized macrophages that are unique to diabetes and obesity. Advantages and disadvantages of the currently most widely used metabolite analysis approaches are highlighted. We further describe how their combined use may serve to provide a comprehensive overview of the metabolic changes that take place intracellularly during macrophage activation in conditions like diabetes and obesity.


Assuntos
Diabetes Mellitus Tipo 2/metabolismo , Metabolismo Energético , Inflamação/metabolismo , Macrófagos/metabolismo , Obesidade/metabolismo , Acetilação , Diabetes Mellitus Tipo 2/imunologia , Epigênese Genética , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica , Glucose/metabolismo , Humanos , Imunomodulação , Inflamação/imunologia , Insulina/metabolismo , Resistência à Insulina , Ativação de Macrófagos , Espectrometria de Massas/métodos , Redes e Vias Metabólicas , Obesidade/imunologia , Fosforilação Oxidativa , Consumo de Oxigênio , Processamento de Proteína Pós-Traducional
18.
Cell Rep ; 37(5): 109919, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34731614

RESUMO

Type 2 diabetes mellitus (T2D) is a chronic age-related disorder characterized by hyperglycemia due to the failure of pancreatic beta cells to compensate for increased insulin demand. Despite decades of research, the pathogenic mechanisms underlying T2D remain poorly defined. Here, we use imaging mass cytometry (IMC) with a panel of 34 antibodies to simultaneously quantify markers of pancreatic exocrine, islet, and immune cells and stromal components. We analyze over 2 million cells from 16 pancreata obtained from donors with T2D and 13 pancreata from age-similar non-diabetic controls. In the T2D pancreata, we observe significant alterations in islet architecture, endocrine cell composition, and immune cell constituents. Thus, both HLA-DR-positive CD8 T cells and macrophages are enriched intra-islet in the T2D pancreas. These efforts demonstrate the utility of IMC for investigating complex events at the cellular level in order to provide insights into the pathophysiology of T2D.


Assuntos
Linfócitos T CD8-Positivos/patologia , Diabetes Mellitus Tipo 2/patologia , Citometria de Fluxo , Células Secretoras de Glucagon/patologia , Células Secretoras de Insulina/patologia , Macrófagos/patologia , Análise de Célula Única , Adolescente , Adulto , Idoso , Biomarcadores/análise , Linfócitos T CD8-Positivos/imunologia , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/imunologia , Feminino , Imunofluorescência , Células Secretoras de Glucagon/imunologia , Antígenos HLA-DR/análise , Humanos , Células Secretoras de Insulina/imunologia , Macrófagos/imunologia , Masculino , Microscopia de Fluorescência , Pessoa de Meia-Idade , Adulto Jovem
19.
Cells ; 10(11)2021 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-34831154

RESUMO

The dermis is the connective layer between the epidermis and subcutis and harbours nerve endings, glands, blood vessels, and hair follicles. The most abundant cell type is the fibroblast. Dermal fibroblasts have a versatile portfolio of functions within the dermis that correspond with different types of cells by either direct contact or by autocrine and paracrine signalling. Diabetic skin is characterized by itching, numbness, ulcers, eczema, and other pathophysiological changes. These pathogenic phenotypes have been associated with the effects of the reactive glucose metabolite methylglyoxal (MGO) on dermal cells. In this study, dermal fibroblasts were isolated from diabetic and non-diabetic human donors. Cultured dermal fibroblasts from diabetic donors exhibited reduced insulin-induced glucose uptake and reduced expression of the insulin receptor. This diabetic phenotype persists under cell culture conditions. Secretion of IL-6 was increased in fibroblasts from diabetic donors. Increased secretion of IL-6 and MIF was also observed upon the treatment of dermal fibroblasts with MGO, suggesting that MGO is sufficient for triggering these immunomodulatory responses. Remarkably, MIF treatment resulted in decreased activity of MGO-detoxifying glyoxalase-1. Given that reduced glyoxalase activity results in increased MGO levels, these findings suggested a positive-feedback loop for MGO generation, in which MIF, evoked by MGO, in turn blocks MGO-degrading glyoxalase activity. Finally, secretion of procollagen Type I C-Peptide (PICP), a marker of collagen production, was reduced in fibroblast from diabetic donors. Remarkably, treatment of fibroblasts with either MGO or MIF was sufficient for inducing reduced PICP levels. The observations of this study unravel a signalling network in human dermal fibroblasts with the metabolite MGO being sufficient for inflammation and delayed wound healing, hallmarks of T2D.


Assuntos
Derme/patologia , Diabetes Mellitus Tipo 2/imunologia , Fibroblastos/patologia , Imunomodulação , Doadores de Tecidos , Cicatrização/imunologia , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Glucose/metabolismo , Humanos , Imunomodulação/efeitos dos fármacos , Insulina/metabolismo , Interleucina-6/metabolismo , Lactoilglutationa Liase/metabolismo , Fatores Inibidores da Migração de Macrófagos/metabolismo , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/metabolismo , Pró-Colágeno/metabolismo , Aldeído Pirúvico/farmacologia , Receptor de Insulina/metabolismo , Transdução de Sinais/efeitos dos fármacos , Cicatrização/efeitos dos fármacos
20.
PLoS One ; 16(10): e0258812, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34669745

RESUMO

Secretory IgA (SIgA) is released into mucosal surfaces where its function extends beyond that of host defense to include the shaping of resident microbial communities by mediating exclusion/inclusion of respective microbes and regulating bacterial gene expression. In this capacity, SIgA acts as the fulcrum on which host immunity and the health of the microbiota are balanced. We recently completed an analysis of the gut and salivary IgA-Biomes (16S rDNA sequencing of SIgA-coated/uncoated bacteria) in Mexican-American adults that identified IgA-Biome differences across the glycemic spectrum. As Th17:Treg ratio imbalances are associated with gut microbiome dysbiosis and chronic inflammatory conditions such as type 2 diabetes, the present study extends our prior work by examining the impact of Th17:Treg ratios (pro-inflammatory:anti-inflammatory T-cell ratios) and the SIgA response (Th17:Treg-SIgA axis) in shaping microbial communities. Examining the impact of Th17:Treg ratios (determined by epigenetic qPCR lymphocyte subset quantification) on the IgA-Biome across diabetes phenotypes identified a proportional relationship between Th17:Treg ratios and alpha diversity in the stool IgA-Biome of those with dysglycemia, significant changes in community composition of the stool and salivary microbiomes across glycemic profiles, and genera preferentially abundant by T-cell inflammatory phenotype. This is the first study to associate epigenetically quantified Th17:Treg ratios with both the larger and SIgA-fractionated microbiome, assess these associations in the context of a chronic inflammatory disease, and offers a novel frame through which to evaluate mucosal microbiomes in the context of host responses and inflammation.


Assuntos
Bactérias/classificação , Diabetes Mellitus Tipo 2/imunologia , Imunoglobulina A Secretora/metabolismo , RNA Ribossômico 16S/genética , Análise de Sequência de DNA/métodos , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Adulto , Bactérias/genética , Bactérias/isolamento & purificação , DNA Bacteriano/genética , DNA Ribossômico/genética , Diabetes Mellitus Tipo 2/microbiologia , Epigênese Genética , Feminino , Microbioma Gastrointestinal , Humanos , Masculino , Americanos Mexicanos , Pessoa de Meia-Idade , Filogenia
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