RESUMO
Chronic inflammation has long been considered the characteristic feature of type II diabetes mellitus (T2DM) Immunopathogenesis. Pro-inflammatory cytokines are considered the central drivers of the inflammatory cascade leading to ß-cell dysfunction and insulin resistance (IR), two major pathologic events contributing to T2DM. Analyzing the cytokine profile of T2DM patients has also introduced interleukin-17 (IL-17) as an upstream regulator of inflammation, regarding its role in inducing the nuclear factor-kappa B (NF-κB) pathway. In diabetic tissues, IL-17 induces the expression of inflammatory cytokines and chemokines. Hence, IL-17 can deteriorate insulin signaling and ß-cell function by activating the JNK pathway and inducing infiltration of neutrophils into pancreatic islets, respectively. Additionally, higher levels of IL-17 expression in patients with diabetic complications compared to non-complicated individuals have also proposed a role for IL-17 in T2DM complications. Here, we highlight the role of IL-17 in the Immunopathogenesis of T2DM and corresponding pathways, recent advances in preclinical and clinical studies targeting IL-17 in T2DM, and corresponding challenges and possible solutions.
Assuntos
Diabetes Mellitus Tipo 2 , Interleucina-17 , Humanos , Diabetes Mellitus Tipo 2/imunologia , Interleucina-17/imunologia , Animais , Inflamação/imunologia , Células Secretoras de Insulina/imunologia , Células Secretoras de Insulina/metabolismo , Células Secretoras de Insulina/patologia , Complicações do Diabetes/imunologia , Resistência à Insulina/imunologia , Transdução de Sinais/imunologiaRESUMO
People with diabetes feature a life-risking susceptibility to respiratory viral infection, including influenza and SARS-CoV-2 (ref. 1), whose mechanism remains unknown. In acquired and genetic mouse models of diabetes, induced with an acute pulmonary viral infection, we demonstrate that hyperglycaemia leads to impaired costimulatory molecule expression, antigen transport and T cell priming in distinct lung dendritic cell (DC) subsets, driving a defective antiviral adaptive immune response, delayed viral clearance and enhanced mortality. Mechanistically, hyperglycaemia induces an altered metabolic DC circuitry characterized by increased glucose-to-acetyl-CoA shunting and downstream histone acetylation, leading to global chromatin alterations. These, in turn, drive impaired expression of key DC effectors including central antigen presentation-related genes. Either glucose-lowering treatment or pharmacological modulation of histone acetylation rescues DC function and antiviral immunity. Collectively, we highlight a hyperglycaemia-driven metabolic-immune axis orchestrating DC dysfunction during pulmonary viral infection and identify metabolic checkpoints that may be therapeutically exploited in mitigating exacerbated disease in infected diabetics.
Assuntos
Células Dendríticas , Complicações do Diabetes , Diabetes Mellitus , Suscetibilidade a Doenças , Hiperglicemia , Pulmão , Viroses , Animais , Camundongos , Acetilcoenzima A/metabolismo , Acetilação , Cromatina/genética , Cromatina/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Complicações do Diabetes/imunologia , Complicações do Diabetes/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/imunologia , Diabetes Mellitus/metabolismo , Glucose/metabolismo , Histonas/metabolismo , Hiperglicemia/complicações , Hiperglicemia/imunologia , Hiperglicemia/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/virologia , Linfócitos T/imunologia , Viroses/complicações , Viroses/imunologia , Viroses/mortalidade , Vírus/imunologia , Modelos Animais de Doenças , HumanosRESUMO
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 InsulinaRESUMO
IL-38 is a recently discovered, novel anti-inflammatory cytokine, which belongs to the IL-1ß family. The role played by this cytokine in diabetes-tuberculosis nexus is not known. Serum levels of IL-38, TNF-α, IL-6, and IL-1ß in Normal Glucose Tolerance (NGT) and chronic Diabetes (DM) subjects, both with and without latent tuberculosis (LTB) (n = 256) were quantified by ELISA. While, serum levels of IL-38 were significantly reduced, the levels of TNF-α, IL-6, and IL-1ß were not altered, in LTB infected diabetes patients. While no significant secretion of IL-38 was detected in the quantiferon supernatant, secretion of TNF-α, IL-6, and IL-1ß was significantly reduced in LTB infected diabetes patients. The decreased systemic levels of IL-38 and reduced in vitro secretion of other pro-inflammatory cytokines might represent a crucial pathway associated with diabetes-tuberculosis nexus.
Assuntos
Citocinas , Diabetes Mellitus , Interleucinas , Tuberculose Latente , Citocinas/sangue , Complicações do Diabetes/imunologia , Diabetes Mellitus/sangue , Diabetes Mellitus/imunologia , Ensaio de Imunoadsorção Enzimática , Humanos , Interleucinas/sangue , Interleucinas/imunologia , Tuberculose Latente/sangue , Tuberculose Latente/complicações , Tuberculose Latente/imunologia , Fator de Necrose Tumoral alfaAssuntos
Anticorpos Anticardiolipina/sangue , Infarto Cerebral/sangue , Infarto Cerebral/imunologia , Idoso , Idoso de 80 Anos ou mais , Coagulação Sanguínea/imunologia , Plaquetas/imunologia , Plaquetas/metabolismo , Infarto Cerebral/complicações , Infarto Cerebral/diagnóstico , Técnicas de Laboratório Clínico , Creatina Quinase/sangue , Creatina Quinase/imunologia , Complicações do Diabetes/imunologia , Diabetes Mellitus/imunologia , Feminino , Ácido Fólico/sangue , Ácido Fólico/imunologia , Homocisteína/sangue , Homocisteína/imunologia , Humanos , Hipertensão/complicações , Hipertensão/imunologia , Imunidade , L-Lactato Desidrogenase/sangue , L-Lactato Desidrogenase/imunologia , Lipídeos/sangue , Lipídeos/imunologia , Masculino , Pessoa de Meia-Idade , Hormônios Tireóideos/sangue , Hormônios Tireóideos/imunologia , Vitamina B 12/sangue , Vitamina B 12/imunologiaRESUMO
BACKGROUND: It is an incontrovertible fact that the Rhino Orbital Cerebral Mucormycosis (ROCM) upsurge is being seen in the context of COVID-19 in India. Briefly presented is evidence that in patients with uncontrolled diabetes, a dysfunctional immune system due to SARS-COV-2 and injudicious use of corticosteroids may be largely responsible for this malady. OBJECTIVE: To find the possible impact of COVID 19 infection and various co-morbidities on occurrence of ROCM and demonstrate the outcome based on medical and surgical interventions. METHODOLOGY: Prospective longitudinal study included patients diagnosed with acute invasive fungal rhinosinusitis after a recent COVID-19 infection. Diagnostic nasal endoscopy (DNE) was performed on each patient and swabs were taken and sent for fungal KOH staining and microscopy. Medical management included Injection Liposomal Amphotericin B, Posaconazole and Voriconazole. Surgical treatment was restricted to patients with RT PCR negative results for COVID-19. Endoscopic, open, and combined approaches were utilized to eradicate infection. Follow-up for survived patients was maintained regularly for the first postoperative month. RESULTS: Out of total 131 patients, 111 patients had prior history of SARS COVID 19 infection, confirmed with a positive RT-PCR report and the rest 20 patients had no such history. Steroids were received as a part of treatment in 67 patients infected with COVID 19. Among 131 patients, 124 recovered, 1 worsened and 6 died. Out of 101 known diabetics, 98 recovered and 3 had fatal outcomes. 7 patients with previous history of COVID infection did not have any evidence of Diabetes mellitus, steroid intake or any other comorbidity. CONCLUSION: It can be concluded that ROCM upsurge seen in the context of COVID-19 in India was mainly seen in patients with uncontrolled diabetes, a dysfunctional immune system due to SARS-COV-2 infection and injudicious use of corticosteroids.
Assuntos
COVID-19/imunologia , Mucormicose/imunologia , Corticosteroides/efeitos adversos , Antifúngicos/uso terapêutico , COVID-19/epidemiologia , Complicações do Diabetes/imunologia , Diagnóstico por Imagem , Endoscopia , Feminino , Humanos , Índia/epidemiologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Mucormicose/tratamento farmacológico , Mucormicose/epidemiologia , Pandemias , Estudos Prospectivos , Fatores de Risco , SARS-CoV-2Assuntos
Complicações do Diabetes , Dermatoses Faciais/microbiologia , Infecções por Mycobacterium/diagnóstico , Mycobacterium , Dermatopatias Bacterianas/diagnóstico , Úlcera Cutânea/microbiologia , Idoso , Complicações do Diabetes/sangue , Complicações do Diabetes/imunologia , Diabetes Mellitus/sangue , Diabetes Mellitus/imunologia , Dermatoses Faciais/diagnóstico , Dermatoses Faciais/patologia , Feminino , Controle Glicêmico , Humanos , Hospedeiro Imunocomprometido , Infecções por Mycobacterium/patologia , Dermatopatias Bacterianas/patologia , Úlcera Cutânea/diagnóstico , Úlcera Cutânea/patologiaRESUMO
Anti-viral monoclonal antibody (mAb) treatments may provide immediate but short-term immunity from coronavirus disease 2019 (COVID-19) in high-risk populations, such as people with diabetes and the elderly; however, data on their efficacy in these populations are limited. We demonstrate that prophylactic mAb treatment blocks viral replication in both the upper and lower respiratory tracts in aged, type 2 diabetic rhesus macaques. mAb infusion dramatically curtails severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-mediated stimulation of interferon-induced chemokines and T cell activation, significantly reducing development of interstitial pneumonia. Furthermore, mAb infusion significantly dampens the greater than 3-fold increase in SARS-CoV-2-induced effector CD4 T cell influx into the cerebrospinal fluid. Our data show that neutralizing mAbs administered preventatively to high-risk populations may mitigate the adverse inflammatory consequences of SARS-CoV-2 exposure.
Assuntos
Anticorpos Monoclonais/uso terapêutico , COVID-19/prevenção & controle , SARS-CoV-2/imunologia , Envelhecimento/imunologia , Animais , COVID-19/líquido cefalorraquidiano , COVID-19/complicações , COVID-19/imunologia , Complicações do Diabetes/imunologia , Complicações do Diabetes/virologia , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/imunologia , Feminino , Humanos , Ativação Linfocitária , Macaca mulatta , Masculino , Neurite (Inflamação)/imunologia , Neurite (Inflamação)/prevenção & controle , Profilaxia Pré-Exposição , Linfócitos T/imunologia , Replicação Viral/imunologiaRESUMO
Acute pancreatitis (AP) is one of the leading causes of hospital admission, 20% of which could progress to the severe type with extensive acinar cell necrosis. Clinical studies have reported that diabetes is an independent risk factor of the incidence of AP and is associated with higher severity than nondiabetic subjects. However, how diabetes participates in AP progression is not well defined. To investigate this question, wild-type (wt) and diabetic db/db mice at the age of 16 weeks were used in the study. AP was induced in wt recipients by 10 injections of 50 µg/kg caerulein with a 1 h interval. One hour after the last caerulein injection, bone marrow cells (BMC) isolated from wt and db/db mice were injected intraperitoneally into the recipients (1 × 107cells/recipient). The recipients with no BMC injection served as controls. Thirteen hours after BMC injection, serum lipase activity was 1.8- and 1.3-folds higher in mice that received db/db BMC, compared with those with no injection and wt BMC injection, respectively (p ≤ 0.02 for both). By H&E staining, the overall severity score was 14.7 for no cell injection and 16.6 for wt BMC injection and increased to 22.6 for db/db BMC injection (p ≤ 0.002 for both). In particular, mice with db/db BMC injection developed more acinar cell necrosis and vacuolization than the other groups (p ≤ 0.03 for both). When sections were stained with an antibody against myeloperoxidase (MPO), the density of MPO+ cells in pancreatitis was 1.9- and 1.6-folds higher than wt BMC and no BMC injection groups, separately (p ≤ 0.02 for both). Quantified by ELISA, db/db BMC produced more IL-6, GM-CSF, and IL-10 compared with wt BMC (p ≤ 0.04 for all). In conclusion, BMC of db/db mice produced more inflammatory cytokines. In response to acinar cell injury, diabetic BMC aggravated the inflammation cascade and acinar cell injury, leading to the progression of acute pancreatitis.
Assuntos
Células da Medula Óssea/imunologia , Complicações do Diabetes/imunologia , Pancreatite/imunologia , Animais , Células da Medula Óssea/metabolismo , Transplante de Medula Óssea , Ceruletídeo/administração & dosagem , Ceruletídeo/toxicidade , Citocinas/metabolismo , Complicações do Diabetes/patologia , Modelos Animais de Doenças , Progressão da Doença , Humanos , Injeções Intraperitoneais , Masculino , Camundongos , Necrose , Pâncreas/efeitos dos fármacos , Pâncreas/imunologia , Pâncreas/patologia , Pancreatite/induzido quimicamente , Pancreatite/patologiaRESUMO
BACKGROUND: It is plausible that gene polymorphisms in tumor necrosis factor-α (TNF-α), interleukin (IL)-1, IL-6, IL-8, and IL-18 may affect predisposition to microvascular complications of diabetes mellitus (DM), but the results of the so far published studies remain controversial. OBJECTIVES: We conducted this meta-analysis to clarify relationships between TNF-α/IL-1/IL-4/IL-8/IL-18 polymorphisms and predisposition to microvascular complications of DM by pooling the findings of eligible studies. METHODS: A comprehensive search of PubMed, Embase, Web of Science, and CNKI was endorsed by us to identify already published studies. Forty-nine studies were found to be eligible for the meta-analyses. RESULTS: The pooled meta-analyses results showed that genotypic frequencies of TNF-α -238 G/A, TNF-α -308 G/A, TNF-α -1,031 T/C, IL-1A -889 C/T, IL-1B -511 C/T, IL-6 -572 G/C, and IL-18 -137 G/C polymorphisms among patients with diabetic nephropathy (DN) and controls differed significantly. Moreover, genotypic frequencies of TNF-α -238 G/A and IL-8 -251 A/T polymorphisms among patients with diabetic retinopathy (DR) and controls also differed significantly. CONCLUSIONS: This meta-analysis suggested that TNF-α -238 G/A, TNF-α -308 G/A, TNF-α -1,031 T/C, IL-1A -889 C/T, IL-1B -511 C/T, IL-6 -572 G/C, and IL-18 -137 G/C polymorphisms may affect predisposition of DN. Moreover, TNF-α -238 G/A and IL-8 -251 A/T polymorphisms may affect predisposition of DR.
Assuntos
Citocinas/genética , Complicações do Diabetes/genética , Doenças Vasculares/genética , Complicações do Diabetes/imunologia , Predisposição Genética para Doença , Humanos , Microvasos , Doenças Vasculares/etiologia , Doenças Vasculares/imunologiaAssuntos
COVID-19/complicações , Hospedeiro Imunocomprometido , Mucormicose/etiologia , Antifúngicos/uso terapêutico , COVID-19/imunologia , Complicações do Diabetes/imunologia , Complicações do Diabetes/microbiologia , Humanos , Mucormicose/complicações , Mucormicose/diagnóstico , Mucormicose/tratamento farmacológico , Fatores de RiscoAssuntos
COVID-19/epidemiologia , Mucormicose/epidemiologia , Sindemia , Antibacterianos/uso terapêutico , COVID-19/prevenção & controle , Comorbidade , Dexametasona/uso terapêutico , Complicações do Diabetes/imunologia , Glucocorticoides/uso terapêutico , Humanos , Hospedeiro Imunocomprometido , Índia/epidemiologia , Mucormicose/tratamento farmacológico , Mucormicose/prevenção & controle , Uso Excessivo de Medicamentos Prescritos , Fatores de Risco , SARS-CoV-2 , Tratamento Farmacológico da COVID-19RESUMO
OBJECTIVES: Intracerebral hemorrhage (ICH) induced by diabetes results in further brain injury and nerve cell death. Bone marrow mesenchymal stem cell (BMSC) transplantation contributes to attenuating neurological deficits after ICH. This study investigated the mechanism of extracellular vesicles (EVs) derived from BMSCs in reducing neuroinflammation after diabetic ICH. METHODS: BMSC-EVs were isolated and identified. The rat model of db/db-ICH was established and the model rats were administered with EVs. miR-183-5p expression in brain tissues of db/db-ICH rats was detected. The brain injury of db/db-ICH rats was evaluated by measuring neurobehavioral score, brain water content and inflammatory factors. BV2 cells were cultured in vitro to establish high-glucose (HG)-Hemin-BV2 cell model. The levels of reactive oxygen species (ROS) and inflammatory factors in BV2 cells were measured, and BV2 cell viability and apoptosis were assessed. The targeting relationship between miR-183-5p and PDCD4 was predicted and verified. The activation of PDCD4/NLRP3 pathway in rat brain tissues and BV2 cells was detected. RESULTS: miR-183-5p expression was reduced in db/db-ICH rats brain tissues. BMSC-EVs ameliorated cranial nerve function, decreased brain water content and repressed inflammatory response by carrying miR-183-5p. BMSC-EVs mitigated HG-Hemin-BV2 cell injury, reduced ROS level and suppressed inflammatory response. miR-183-5p targeted PDCD4. PDCD4 promoted BV2 cell inflammation by activating the NLRP3 pathway. BMSC-EVs inhibited HG-Hemin-BV2 cell inflammation through the miR-183-5p/PDCD4/NLRP3 pathway, and inhibition of miR-183-5p reversed the protective effect of EVs. CONCLUSION: BMSC-EVs carried miR-183-5p into db/db-ICH rat brain tissues and repressed the NLRP3 pathway by targeting PDCD4, thus alleviating neuroinflammation after diabetic ICH.
Assuntos
Proteínas Reguladoras de Apoptose/metabolismo , Hemorragia Cerebral , Complicações do Diabetes , Vesículas Extracelulares/transplante , MicroRNAs/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Animais , Encéfalo/imunologia , Encéfalo/metabolismo , Células Cultivadas , Hemorragia Cerebral/etiologia , Hemorragia Cerebral/imunologia , Hemorragia Cerebral/metabolismo , Hemorragia Cerebral/terapia , Complicações do Diabetes/imunologia , Complicações do Diabetes/metabolismo , Transplante de Células-Tronco Mesenquimais/métodos , Células-Tronco Mesenquimais/ultraestrutura , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/terapia , Fatores de Proteção , Ratos , Transdução de SinaisRESUMO
Increased accumulation of advanced glycation end products (AGEs) in diabetic skin is closely related to delayed wound healing. Studies have shown that the concentration of AGEs is elevated in the skin tissues and not subcutaneous tissues in refractory diabetic wounds, which suggests there may be a causal relationship between the two. In the present study, in vitro experiments revealed that AGEs activated neutrophils, and the migratory and adhesive functions of neutrophils decreased once AGE levels reached a certain threshold. Different levels of AGE expression differentially affected the function of neutrophils. Messenger RNA (mRNA) sequencing analysis combined with real-time polymerase chain reaction (PCR) showed that poliovirus receptor (PVR/CD155) and CTNND1, which play a role in migration- and adhesion-related signaling pathways, were decreased following AGE stimulation. Consequently, neutrophils cannot effectively stimulate the formation of the inflammatory belt needed to remove necrotic tissues and defend against foreign microorganisms within diabetic chronic wounds. In addition, this phenomenon may be related to the differential accumulation of AGEs in different layers of the skin.
Assuntos
Complicações do Diabetes/imunologia , Diabetes Mellitus Experimental/complicações , Produtos Finais de Glicação Avançada/metabolismo , Neutrófilos/imunologia , Pele/patologia , Animais , Cateninas/metabolismo , Agregação Celular/imunologia , Linhagem Celular Tumoral , Movimento Celular/imunologia , Complicações do Diabetes/patologia , Diabetes Mellitus Experimental/induzido quimicamente , Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Experimental/patologia , Humanos , Masculino , Ratos , Receptores Virais/metabolismo , Pele/citologia , Pele/imunologia , Estreptozocina/administração & dosagem , Estreptozocina/toxicidade , Cicatrização/imunologia , delta CateninaRESUMO
BACKGROUND: End-stage renal disease (ESRD) is associated with alterations in T-cell immunity, including increased CD28null and reduced regulatory T cells (Tregs). However, whether immune disturbances are due to ESRD or primary disease is not yet clear. As diabetes mellitus is the leading cause of ESRD, we evaluated its impact on the immune profile of ESRD patients. METHODS: CD28null, Tregs, and natural killer cells were initially analyzed by flow cytometry in 30 predialysis ESRD patients due to diabetes (DM), 30 non-DM (NDM), and 25 healthy controls. Measurements were repeated after 6 months on hemodialysis (HD) or peritoneal dialysis (CAPD). RESULTS: The percentage of CD4 + CD28null cells, CD8 + CD28null cells, and Tregs showed significant differences in DM, NDM, and controls; mean rank 33.71 vs. 25.68 vs. 18.88, p = 0.006, 37.79 vs. 28.82 vs. 17.08, p = 0.008, and 20.79 vs. 26.12 vs. 41.33, p = 0.001, respectively. DM vs. NDM had increased CD4 + CD28null and CD8 + CD28null cells, 11.5% (1.5%-24%) vs. 4.1% (0-42.3%), p = 0.02 and 61.3% (24%-76%) vs. 43% (5.7%-85%), p = 0.04, respectively. After 6 months on HD but not CAPD, DM showed a significant further increase in CD4 + CD28null cells, from 30 (14-100) to 52.7 (15-203), p = 0.02; and CD8 + CD28null cells, from 137 (56-275) to 266 (103-456), p = 0.01. CONCLUSIONS: Diabetes mellitus affects T-cell subtypes even at predialysis stage, though changes become more prominent after commencement on HD.
Assuntos
Complicações do Diabetes/imunologia , Diabetes Mellitus/imunologia , Falência Renal Crônica/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Antígenos CD28/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Complicações do Diabetes/genética , Complicações do Diabetes/patologia , Diabetes Mellitus/genética , Diabetes Mellitus/patologia , Feminino , Citometria de Fluxo , Humanos , Falência Renal Crônica/etiologia , Falência Renal Crônica/genética , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Diálise RenalRESUMO
As part of the centennial celebration of insulin's discovery, this review summarizes the current understanding of the genetics, pathogenesis, treatment, and outcomes in type 1 diabetes (T1D). T1D results from an autoimmune response that leads to destruction of the ß cells in the pancreatic islet and requires lifelong insulin therapy. While much has been learned about T1D, it is now clear that there is considerable heterogeneity in T1D with regard to genetics, pathology, response to immune-based therapies, clinical course, and susceptibility to diabetes-related complications. This Review highlights knowledge gaps and opportunities to improve the understanding of T1D pathogenesis and outlines emerging therapies to treat or prevent T1D and reduce the burden of T1D.
Assuntos
Complicações do Diabetes/imunologia , Diabetes Mellitus Tipo 1/imunologia , Células Secretoras de Insulina/imunologia , Complicações do Diabetes/patologia , Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Tipo 1/prevenção & controle , Humanos , Insulina/imunologia , Insulina/uso terapêutico , Células Secretoras de Insulina/patologiaRESUMO
Uncontrolled diabetes results in several metabolic alterations including hyperglycemia. Indeed, several preclinical and clinical studies have suggested that this condition may induce susceptibility and the development of more aggressive infectious diseases, especially those caused by some bacteria (including Chlamydophila pneumoniae, Haemophilus influenzae, and Streptococcus pneumoniae, among others) and viruses [such as coronavirus 2 (CoV2), Influenza A virus, Hepatitis B, etc.]. Although the precise mechanisms that link glycemia to the exacerbated infections remain elusive, hyperglycemia is known to induce a wide array of changes in the immune system activity, including alterations in: (i) the microenvironment of immune cells (e.g., pH, blood viscosity and other biochemical parameters); (ii) the supply of energy to infectious bacteria; (iii) the inflammatory response; and (iv) oxidative stress as a result of bacterial proliferative metabolism. Consistent with this evidence, some bacterial infections are typical (and/or have a worse prognosis) in patients with hypercaloric diets and a stressful lifestyle (conditions that promote hyperglycemic episodes). On this basis, the present review is particularly focused on: (i) the role of diabetes in the development of some bacterial and viral infections by analyzing preclinical and clinical findings; (ii) discussing the possible mechanisms by which hyperglycemia may increase the susceptibility for developing infections; and (iii) further understanding the impact of hyperglycemia on the immune system.
Assuntos
Infecções Bacterianas/etiologia , COVID-19/etiologia , Complicações do Diabetes/imunologia , Complicações do Diabetes/fisiopatologia , Suscetibilidade a Doenças , Hiperglicemia/complicações , Viroses/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Hematopoietic stem/progenitor cells (HSPCs) participate in cardiovascular (CV) homeostasis and generate different types of blood cells including lymphoid and myeloid cells. Diabetes mellitus (DM) is characterized by chronic increase of pro-inflammatory mediators, which play an important role in the development of CV disease, and increased susceptibility to infections. Here, we aimed to evaluate the impact of DM on the transcriptional profile of HSPCs derived from bone marrow (BM). Total RNA of BM-derived CD34+ stem cells purified from sternal biopsies of patients undergoing coronary bypass surgery with or without DM (CAD and CAD-DM patients) was sequenced. The results evidenced 10566 expressed genes whose 79% were protein-coding genes, and 21% non-coding RNA. We identified 139 differentially expressed genes (p-value < 0.05 and |log2 FC| > 0.5) between the two comparing groups of CAD and CAD-DM patients. Gene Set Enrichment Analysis (GSEA), based on Gene Ontology biological processes (GO-BP) terms, led to the identification of fourteen overrepresented biological categories in CAD-DM samples. Most of the biological processes were related to lymphocyte activation, chemotaxis, peptidase activity, and innate immune response. Specifically, HSPCs from CAD-DM patients displayed reduced expression of genes coding for proteins regulating antibacterial and antivirus host defense as well as macrophage differentiation and lymphocyte emigration, proliferation, and differentiation. However, within the same biological processes, a consistent number of inflammatory genes coding for chemokines and cytokines were up-regulated. Our findings suggest that DM induces transcriptional alterations in HSPCs, which are potentially responsible of progeny dysfunction.
Assuntos
Doenças Cardiovasculares/imunologia , Doença da Artéria Coronariana/imunologia , Complicações do Diabetes/imunologia , Transcriptoma , Idoso , Antígenos CD34/imunologia , Células Sanguíneas/imunologia , Medula Óssea/imunologia , Diferenciação Celular , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Células-Tronco Hematopoéticas/imunologia , Humanos , Inflamação , Linfócitos/imunologia , Masculino , Pessoa de Meia-Idade , Células Mieloides/imunologia , FenótipoRESUMO
CONTEXT: Demonstrating the ability to mount a neutralizing antibody response to SARS-CoV-2 in the presence of diabetes is crucial to understand COVID-19 pathogenesis, reinfection potential, and vaccine development. OBJECTIVE: The aim of this study was to characterize the kinetics and durability of neutralizing antibody (Nab) response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the presence of hyperglycemia. METHODS: Using a lentiviral vector-based SARS-CoV-2 neutralization assay to measure Nabs, we characterized 150 patients randomly selected from a cohort of 509 patients with confirmed COVID-19 pneumonia. We analyzed Nab response according to the presence of diabetes or hyperglycemia, at the time of hospitalization and during the postdischarge follow-up: 1-, 3-, and 6-month outpatient visits. RESULTS: Among 150 randomly selected patients 40 (26.6%) had diabetes. Diabetes (hazard ratio [HR] 8.9, P < .001), glucose levels (HR 1.25 × 1.1 mmol/L, P < .001), and glucose variability (HR 1.17 × 0.6 mmol/L, P < .001) were independently associated with an increased risk of mortality. The neutralizing activity of SARS-CoV-2 antibodies in patients with diabetes was superimposable, as for kinetics and extent, to that of patients without diabetes. It was similar across glucose levels and correlated with the humoral response against the SARS-CoV-2 spike protein. Positivity for Nabs at the time of hospital admission conferred protection on mortality, both in the presence (HR 0.28, P = .046) or absence of diabetes (HR 0.26, P = .030). The longevity of the Nab response was not affected by diabetes. CONCLUSION: Diabetes and hyperglycemia do not affect the kinetics and durability of the neutralizing antibody response to SARS-CoV-2. These findings provide the rational to include patients with diabetes in the early phase of the vaccination campaign against SARS-CoV-2.
Assuntos
Anticorpos Neutralizantes/imunologia , COVID-19/imunologia , Complicações do Diabetes/imunologia , Pneumonia/imunologia , COVID-19/complicações , Complicações do Diabetes/virologia , Feminino , Humanos , Masculino , Pneumonia/complicaçõesRESUMO
Diabetic wounds are characterized by persistent accumulation of proinflammatory monocytes (Mo)/macrophages (MΦ) and impaired healing. However, the mechanisms underlying the persistent accumulation of Mo/MΦ remain poorly understood. In this study, we report that Ly6C+F4/80lo/- Mo/MΦ proliferate at higher rates in wounds of diabetic mice compared with nondiabetic mice, leading to greater accumulation of these cells. Unbiased single cell RNA sequencing analysis of combined nondiabetic and diabetic wound Mo/MΦ revealed a cluster, populated primarily by cells from diabetic wounds, for which genes associated with the cell cycle were enriched. In a screen of potential regulators, CCL2 levels were increased in wounds of diabetic mice, and subsequent experiments showed that local CCL2 treatment increased Ly6C+F4/80lo/- Mo/MΦ proliferation. Importantly, adoptive transfer of mixtures of CCR2-/- and CCR2+/+ Ly6Chi Mo indicated that CCL2/CCR2 signaling is required for their proliferation in the wound environment. Together, these data demonstrate a novel role for the CCL2/CCR2 signaling pathway in promoting skin Mo/MΦ proliferation, contributing to persistent accumulation of Mo/MΦ and impaired healing in diabetic mice.