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1.
Ann Plast Surg ; 88(5 Suppl 5): S466-S472, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35502953

RESUMO

BACKGROUND: Acellular dermal matrix (ADM) supported implant-based reconstruction remains the most commonly performed mode of reconstruction after breast cancer. Acellular dermal matrix clinical usage has reported benefits but requires rapid and efficient vascular and cellular incorporation into the recipient to have the best outcomes. Orderly transition from M1 to M2 macrophage phenotypic profile, coordinated in part by interleukin 4 (IL-4), is an important component of vascular stabilization and remodeling. Using the ADM substrate as a delivery device for immunomodulation of macrophage phenotype holds the potential to improve integration. METHODS: Interleukin 4 was adsorbed onto ADM samples and drug elution curves were measured. Next, experimental groups of 8 C57BL/6 mice had 5-mm ADM discs surgically placed in a dorsal window chamber with a vascularized skin flap on one side and a plastic cover slip on the other in a model of implant-based breast reconstruction. Group 1 consisted of IL-4 (5 µg) adsorbed into the ADM preoperatively and group 2 consisted of an untreated ADM control. Serial gross examinations were performed with histology at day 21 for markers of vascularization, mesenchymal cell infiltration, and macrophage lineage. RESULTS: Drug elution curves showed sustained IL-4 release for 10 days after adsorption. Serial gross examination showed similar rates of superficial vascular investment of the ADM beginning at the periphery by day 14 and increasing through day 21. Interleukin-4 treatment led to significantly increased CD31 staining of vascular endothelial cells within the ADM over the control group (P < 0.05) at 21 days. Although vimentin staining did not indicate a significant increase in fibroblasts overall, IL-4 did result in a significant increase in expression of α-smooth muscle actin. The expression of macrophage phenotype markers Arginase1 and iNOS present within the ADM were not significantly affected by IL-4 treatment at the day 21 time point. CONCLUSIONS: Acellular dermal matrix has the potential to be used for immunomodulatory cytokine delivery during the timeframe of healing. Using implanted ADM as a delivery vehicle to drive IL-4 mediated angiogenesis and vascular remodeling significantly enhanced vascularity within the ADM substrate.


Assuntos
Derme Acelular , Interleucina-4 , Derme Acelular/efeitos dos fármacos , Animais , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Imunomodulação , Interleucina-4/imunologia , Interleucina-4/farmacocinética , Interleucina-4/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Remodelação Vascular
2.
Cell Death Dis ; 13(5): 454, 2022 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-35550500

RESUMO

T-cell immunoglobulin mucin-3 (Tim-3) plays roles in the functional regulation of both adaptive and innate immune cells and is greatly involved in many diseases. However, the precise roles of Tim-3 on macrophages (Mφs) in pregnancy remain unstated. In the current study, we found the higher frequency of Tim-3+ decidual Mφs (dMφs) in response to trophoblasts. The reduced abundance of Tim-3 on Mφs was accompanied by disordered anti- and pro-inflammatory cytokine profiles in miscarriage. Adoptive transfer of Tim-3+Mφs, but not Tim-3-Mφs, relieved murine embryo absorption induced by Mφ depletion. Our flow cytometry results and the extensive microarray analysis confirmed that Tim-3+ and Tim-3-dMφs were neither precisely pro-inflammatory (M1) nor anti-inflammatory (M2) Mφs. However, with higher CD132 expression, Tim-3+dMφs subset induced Th2 and Treg bias in decidual CD4+T cells and promoted pregnancy maintenance. Blockade of Tim-3 or CD132 pathways leaded to the dysfunction of maternal-fetal tolerance and increased fetal loss. These findings underscored the important roles of Tim-3 in regulating dMφ function and maintaining normal pregnancy, and suggested that Tim-3 on Mφs is a potential biomarker for diagnosis of miscarriage. Our study also emphasized the importance of careful consideration of reproductive safety when choosing immune checkpoint blockade therapies in real world clinical care. Though IL-4 treated Tim-3-Mφs could rescue the fetal resorption induced by Mφ depletion, whether IL-4 represent novel therapeutic strategy to prevent pregnancy loss induced by checkpoint inhibition still needs further research.


Assuntos
Aborto Espontâneo , Receptor Celular 2 do Vírus da Hepatite A , Macrófagos , Linfócitos T Reguladores , Células Th2 , Animais , Decídua , Feminino , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Interleucina-4/imunologia , Macrófagos/imunologia , Camundongos , Gravidez , Manutenção da Gravidez , Linfócitos T Reguladores/imunologia , Células Th2/imunologia
3.
Front Immunol ; 13: 798813, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35237261

RESUMO

A successful vaccination would represent the most efficient means to control the pandemic of Coronavirus Disease-19 (COVID-19) that led to millions of deaths worldwide. Novel mRNA-based vaccines confer protective immunity against SARS-CoV-2, but whether immunity is immediately effective and how long it will remain in recipients are uncertain. We sought to assess the effectiveness of a two-dose regimen since the boosts are often delayed concerning the recommended intervals. Methods: A longitudinal cohort of healthcare workers (HCW, N = 46; 30.4% men; 69.6% women; mean age 36.05 ± 2.2 years) with no SARS-CoV-2 infection as documented by negative polymerase chain reaction was immunophenotyped in PBMC once a week for 4 weeks from the prime immunization (Pfizer mRNA BNT162b2) and had received 2 doses, to study the kinetic response. Results: We identified three risk groups to develop SARS-CoV-2 infection IgG+-based (late responders, R-; early responders, R+; pauci responders, PR). In all receipts, amplification of B cells and NK cells, including IL4-producing B cells and IL4-producing CD8+ T cells, is early stimulated by the vaccine. After the boost, we observed a growing increase of NK cells but a resistance of T cells, IFNγ-producing CD4+T cells, and IFNγ-producing NK cells. Also, hematologic parameters decline until the boost. The positive association of IFNγ-producing NK with IFNγ-producing CD4+T cells by the multiple mixed-effect model, adjusted for confounders (p = 0.036) as well as the correlation matrix (r = 0.6, p < 0.01), suggests a relationship between these two subsets of lymphocytes. Conclusions: These findings introduce several concerns about policy delay in vaccination: based on immunological protection, B cells and the persistent increase of NK cells during 2 doses of the mRNA-based vaccine could provide further immune protection against the virus, while CD8+ T cells increased slightly only in the R+ and PR groups.


Assuntos
/imunologia , Imunização , Interferon gama/imunologia , Células Matadoras Naturais/imunologia , SARS-CoV-2/imunologia , Linfócitos T/imunologia , Adulto , Linfócitos B/imunologia , COVID-19/imunologia , COVID-19/prevenção & controle , Feminino , Humanos , Interleucina-4/imunologia , Leucócitos Mononucleares/imunologia , Subpopulações de Linfócitos/imunologia , Masculino , Equilíbrio Th1-Th2
4.
Front Immunol ; 13: 796682, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35250975

RESUMO

In the ongoing coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), natural killer T (NKT) cells act as primary initiators of immune responses. However, a decrease of circulating NKT cells has been observed in COVID-19 different stages, of which the underlying mechanism remains to be elucidated. Here, by performing single-cell RNA sequencing analysis in three large cohorts of COVID-19 patients, we found that increased expression of Tim-3 promotes depletion of NKT cells during the progression stage of COVID-19, which is associated with disease severity and outcome of patients with COVID-19. Tim-3+ NKT cells also expressed high levels of CD147 and CD26, which are potential SARS-CoV-2 spike binding receptors. In the study, Tim-3+ NKT cells showed high enrichment of apoptosis, higher expression levels of mitochondrial genes and caspase genes, with a larger pseudo time value. In addition, Tim-3+ NKT cells in COVID-19 presented a stronger capacity to secrete IFN-γ, IL-4 and IL-10 compared with healthy individuals, they also demonstrated high expression of co-inhibitory receptors such as PD-1, CTLA-4, and LAG-3. Moreover, we found that IL-12 secreted by dendritic cells (DCs) was positively correlated with up-regulated expression of Tim-3 in NKT cells in COVID-19 patients. Overall, this study describes a novel mechanism by which up-regulated Tim-3 expression induced the depletion and dysfunction of NKT cells in COVID-19 patients. These findings not only have possible implications for the prediction of severity and prognosis in COVID-19 but also provide a link between NKT cells and future new therapeutic strategies in SARS-CoV-2 infection.


Assuntos
COVID-19/imunologia , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Células T Matadoras Naturais/imunologia , SARS-CoV-2/imunologia , Humanos , Interferon gama/imunologia , Interleucina-10/imunologia , Interleucina-4/imunologia , Transdução de Sinais/imunologia
5.
Viruses ; 14(2)2022 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-35215787

RESUMO

Porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus (PCVs) are two major viruses that affect pigs. Coinfections between PRRSV and PCV2 are frequently reported in most outbreaks, with clinical presentations involving dyspnea, fever, reduced feed intake, weight loss, and death in fattening pigs. The NADC30-like PRRSV and PCV2d are the main circulating virus strains found in China. This study determines the impact of NADC30-like PRRSV and PCV2d mono-infection and coinfection on the immune system, organ pathology, and viral shedding in five-week-old post-weaned pigs. Pigs were randomly divided into six groups: PBS, PRRSV, PCV2, PRRSV-PCV2 coinfection (co), and PRRSV-PCV2 or PCV2-PRRSV sequential infections. Fever, dyspnea, decreased feed intake, weight loss, and pig deaths occurred in groups infected with PRRSV, Co-PRRSV-PCV2, and PRRSV-PCV2. The viral load was higher in Co-PRRSV-PCV2, PRRSV-PCV2, and PCV2-PRRSV than those mono-infected with PRRSV or PCV2. Additionally, cytokines (IFN-γ, TNF-α, IL-4, and IL-10) produced by pigs under Co-PRRSV-PCV2 and PRRSV-PCV2 groups were more intense than the other groups. Necropsy findings showed hemorrhage, emphysema, and pulmonary adhesions in the lungs of pigs infected with PRRSV. Smaller alveoli and widened lung interstitium were found in the Co-PRRSV-PCV2 and PRRSV-PCV2 groups. In conclusion, PRRSV and PCV2 coinfection and sequential infection significantly increased viral pathogenicity and cytokine responses, resulting in severe clinical signs, lung pathology, and death.


Assuntos
Infecções por Circoviridae/veterinária , Circovirus/fisiologia , Circovirus/patogenicidade , Coinfecção/virologia , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/fisiologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/patogenicidade , Animais , China , Infecções por Circoviridae/genética , Infecções por Circoviridae/imunologia , Infecções por Circoviridae/virologia , Circovirus/genética , Coinfecção/genética , Coinfecção/imunologia , Coinfecção/mortalidade , Feminino , Interleucina-10/genética , Interleucina-10/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Pulmão/imunologia , Pulmão/virologia , Masculino , Síndrome Respiratória e Reprodutiva Suína/genética , Síndrome Respiratória e Reprodutiva Suína/imunologia , Síndrome Respiratória e Reprodutiva Suína/mortalidade , Vírus da Síndrome Respiratória e Reprodutiva Suína/genética , Suínos , Virulência
6.
J Sci Food Agric ; 102(3): 1205-1215, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34346509

RESUMO

BACKGROUND: Resveratrol, a kind of polyphenolic phytoalexin, can be obtained from numerous natural foods. Although resveratrol is demonstrated to have various bioactivities, little is known about the regulation of intestinal barrier function under immunosuppression. The present study is aimed at investigating the regulatory effect of resveratrol on intestinal barrier function in immunosuppression in mice induced by cyclophosphamide. RESULTS: The effects of resveratrol on intestinal biological barrier were evaluated by 16S rRNA and metagenome sequencing analysis. The results showed that resveratrol could improve diversity of the intestinal microbiota and intestinal flora structure by increasing the abundance of probiotics, and resveratrol regulated the function of gut microbiota to resist immunosuppression. Resveratrol could significantly upregulate the secretion of secretory immunoglobulin A and promote the transcriptional levels of test cytokines, including tumor necrosis factor α, interferon γ, interleukin 4 and interleukin 6 in jejunum and ileum mucosa, suggesting improved intestinal immune barrier by resveratrol. The mRNA and protein levels of tight junction proteins involved in intestinal physical barrier function, including zonula occludens 1 (ZO-1), claudin 1 and occludin, were increased after resveratrol treatment. The protein levels of toll-like receptor 4 (TLR4), phosphorylation nuclear factor kappa-B (NF-κB-p65) and inhibitor of nuclear factor kappa-B kinase α were decreased by resveratrol treatment when compared with the untreated group, indicating inhibition of the TLR4/NF-ĸB signaling pathway. CONCLUSION: These results provide new insights into regulation of the intestinal barrier function by resveratrol under immunosuppression and potential applications of resveratrol in recovering intestinal function. © 2021 Society of Chemical Industry.


Assuntos
Ciclofosfamida/efeitos adversos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Resveratrol/administração & dosagem , Animais , Microbioma Gastrointestinal/efeitos dos fármacos , Hospedeiro Imunocomprometido , Interferon gama/genética , Interferon gama/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Mucosa Intestinal/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/genética , Ocludina/genética , Ocludina/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
7.
Haematologica ; 107(4): 816-824, 2022 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-33951888

RESUMO

Cytokines are key regulators of tumor immune surveillance by controlling immune cell activity. Here, we investigated whether interleukin 4 (IL4) has antileukemic activity via immune-mediated mechanisms in an in vivo murine model of acute myeloid leukemia driven by the MLL-AF9 fusion gene. Although IL4 strongly inhibited leukemia development in immunocompetent mice, the effect was diminished in immune-deficient recipient mice, demonstrating that the antileukemic effect of IL4 in vivo is dependent on the host immune system. Using flow cytometric analysis and immunohistochemistry, we revealed that the antileukemic effect of IL4 coincided with an expansion of F4/80+ macrophages in the bone marrow and spleen. To elucidate whether this macrophage expansion was responsible for the antileukemic effect, we depleted macrophages in vivo with clodronate liposomes. Macrophage depletion eliminated the antileukemic effect of IL4, showing that macrophages mediated the IL4-induced killing of leukemia cells. In addition, IL4 enhanced murine macrophage-mediated phagocytosis of leukemia cells in vitro. Global transcriptomic analysis of macrophages revealed an enrichment of signatures associated with alternatively activated macrophages and increased phagocytosis upon IL4 stimulation. Notably, IL4 concurrently induced Stat6-dependent upregulation of CD47 on leukemia cells, which suppressed macrophage activity. Consistent with this finding, combining CD47 blockade with IL4 stimulation enhanced macrophage-mediated phagocytosis of leukemia cells. Thus, IL4 has two counteracting roles in regulating phagocytosis in mice; enhancing macrophage-mediated killing of leukemia cells, but also inducing CD47 expression that protects target cells from excessive phagocytosis. Taken together, our data suggest that combined strategies that activate macrophages and block CD47 have therapeutic potential in acute myeloid leukemia.


Assuntos
Antígeno CD47 , Interleucina-4 , Leucemia Mieloide Aguda , Fagocitose , Animais , Antígeno CD47/metabolismo , Interleucina-4/imunologia , Leucemia Mieloide Aguda/imunologia , Camundongos , Regulação para Cima
8.
Exp Neurol ; 347: 113909, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34717939

RESUMO

Interleukin-4 (IL-4) has garnered interest as a cytokine that mediates regeneration across multiple tissues including peripheral nerve. Within nerve, we previously showed endogenous IL-4 was critical to regeneration across nerve gaps. Here, we determined a generalizable role of IL-4 in nerve injury and regeneration. In wild-type (WT) mice receiving a sciatic nerve crush, IL-4 expressing cells preferentially accumulated within the injured nerve compared to affected sites proximal, such as dorsal root ganglia (DRGs), or distal muscle. Immunohistochemistry and flow cytometry confirmed that eosinophils (CD45+, CD11b+, CD64-, Siglec-F+) were sources of IL-4 expression. Examination of targets for IL-4 within nerve revealed macrophages, as well as subsets of neurons expressed IL-4R, while Schwann cells expressed limited IL-4R. Dorsal root ganglia cultures were exposed to IL-4 and demonstrated an increased proportion of neurons that extended axons compared to cultures without IL-4 (control), as well as longer myelinated axons compared to cultures without IL-4. The role of endogenous IL-4 during nerve injury and regeneration in vivo was assessed following a sciatic nerve crush using IL-4 knockout (KO) mice. Loss of IL-4 affected macrophage accumulation within injured nerve compared to WT mice, as well as shifted macrophage phenotype towards a CD206- phenotype with altered gene expression. Furthermore, this loss of IL-4 delayed initial axon regeneration from the injury crush site and subsequently delayed functional recovery and re-innervation of neuromuscular junctions compared to wild-type mice. Given the role of endogenous IL-4 in nerve regeneration, exogenous IL-4 was administered daily to WT mice following a nerve crush to examine regeneration. Daily IL-4 administration increased early axonal extension and CD206+ macrophage accumulation but did not alter functional recovery compared to untreated mice. Our data demonstrate IL-4 promotes nerve regeneration and recovery after injury.


Assuntos
Interleucina-4/administração & dosagem , Interleucina-4/biossíntese , Regeneração Nervosa/fisiologia , Neuropatia Ciática/metabolismo , Animais , Células Cultivadas , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/metabolismo , Gânglios Espinais/imunologia , Gânglios Espinais/metabolismo , Regulação da Expressão Gênica , Injeções Intraperitoneais , Interleucina-4/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Compressão Nervosa/tendências , Regeneração Nervosa/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Receptores de Interleucina-4/biossíntese , Receptores de Interleucina-4/imunologia , Neuropatia Ciática/tratamento farmacológico , Neuropatia Ciática/imunologia
9.
Virology ; 566: 98-105, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34896902

RESUMO

The innate and acquired immune response induced by a commercial inactivated vaccine against Bovine Herpesvirus-1 (BoHV-1) and protection conferred against the virus were analyzed in cattle. Vaccination induced high levels of BoHV-1 antibodies at 30, 60, and 90 days post-vaccination (dpv). IgG1 and IgG2 isotypes were detected at 90 dpv, as well as virus-neutralizing antibodies. An increase of anti-BoHV-1 IgG1 in nasal swabs was detected 6 days post-challenge in vaccinated animals. After viral challenge, lower virus excretion and lower clinical score were observed in vaccinated as compared to unvaccinated animals, as well as BoHV-1-specific proliferation of lymphocytes and production of IFNγ, TNFα, and IL-4. Downregulation of the expression of endosome Toll-like receptors 8-9 was detected after booster vaccination. This is the first thorough study of the immunity generated by a commercial vaccine against BoHV-1 in cattle.


Assuntos
Anticorpos Neutralizantes/biossíntese , Herpesvirus Bovino 1/imunologia , Vacinas contra Herpesvirus/administração & dosagem , Imunoglobulina G/biossíntese , Rinotraqueíte Infecciosa Bovina/prevenção & controle , Receptor 8 Toll-Like/imunologia , Receptor Toll-Like 9/imunologia , Imunidade Adaptativa/efeitos dos fármacos , Animais , Anticorpos Antivirais , Bovinos , Proliferação de Células , Endossomos/imunologia , Endossomos/metabolismo , Expressão Gênica , Herpesvirus Bovino 1/patogenicidade , Imunidade Inata/efeitos dos fármacos , Imunização Secundária/métodos , Rinotraqueíte Infecciosa Bovina/genética , Rinotraqueíte Infecciosa Bovina/imunologia , Rinotraqueíte Infecciosa Bovina/virologia , Interferon gama/genética , Interferon gama/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Linfócitos/imunologia , Linfócitos/virologia , Masculino , Cavidade Nasal/imunologia , Cavidade Nasal/virologia , Receptor 8 Toll-Like/agonistas , Receptor 8 Toll-Like/genética , Receptor Toll-Like 9/agonistas , Receptor Toll-Like 9/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia , Vacinação/métodos , Vacinas de Produtos Inativados
10.
FEBS Lett ; 596(4): 427-436, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34939667

RESUMO

T helper cells, especially Th1 and Th17 cells, were reported to play a pivotal role in the pathogenesis of inflammatory bowel disease (IBD). However, the underlying factors regulating T cell functions in IBD progression remain to be fully elucidated. Here, we revealed that IL-17RD/Sef exacerbates DSS-induced colitis by regulating the balance of T cell subsets and their secretion of associated cytokines. We also observed that IL-17RD/Sef promotes colitis-associated tumorigenesis and negatively correlates with survival in both mouse and colorectal cancer patients. Our results suggested that IL-17RD/Sef functions as a regulator of T cell subsets to promote the inflammatory responses in the pathogenesis of IBD and colitis-associated colon cancer.


Assuntos
Carcinogênese/imunologia , Colite/imunologia , Proteínas de Membrana/imunologia , Células Th1/imunologia , Células Th17/imunologia , Animais , Carcinogênese/genética , Carcinogênese/patologia , Colite/induzido quimicamente , Colite/genética , Colite/mortalidade , Colo/imunologia , Colo/patologia , Sulfato de Dextrana/administração & dosagem , Modelos Animais de Doenças , Regulação da Expressão Gênica , Humanos , Inflamação , Interferon gama/genética , Interferon gama/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Contagem de Linfócitos , Masculino , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Análise de Sobrevida , Células Th1/patologia , Células Th17/patologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
11.
J Dermatol Sci ; 104(2): 122-131, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34763990

RESUMO

BACKGROUND: Both human and mouse allergic contact dermatitis (ACD) frequently demonstrates a combined type 1 and type 2 immune response. However, the relative importance of type 2 immunity in this setting has been incompletely understood yet. OBJECTIVE: To explore an effector function of type 2 immunity in ACD with mixed type 1/type 2 immune response. METHODS: Gene expression characteristics of contact hypersensitivity (CHS) model was examined by quantitative polymerase chain reaction. Cytokine profile of T cells was analyzed by flow cytometry. The involvement of type 2 immunity was assessed by antibody-mediated cytokine neutralization and cell depletion. The role of specific subset of cutaneous dendritic cells was evaluated using diphtheria toxin-induced cell-depleting mouse strains. RESULTS: Oxazolone-induced CHS revealed a combination of type 1/type 2 gene expression. The severity of oxazolone-induced CHS was ameliorated by neutralization of IL-4 but not of IFN-γ, indicating that type 2 immunity plays a dominant effector function in this mixed type 1/type 2 model. Mechanistically, type 2 effector immunity was mounted by CD301b+Langeirn- dermal dendritic cells in part through thymic stromal lymphopoietin-interleukin 7 receptor alpha signaling-dependent manner. CONCLUSION: Our findings suggest the clinical rationale for targeting type 2 immunity as a relevant therapeutic strategy for the mixed immune phenotype of ACD.


Assuntos
Células Dendríticas/imunologia , Dermatite Alérgica de Contato/genética , Dermatite Alérgica de Contato/imunologia , Animais , Antígenos de Superfície/metabolismo , Dermatite Alérgica de Contato/patologia , Modelos Animais de Doenças , Imunidade/genética , Imunoglobulinas/metabolismo , Interferon gama/genética , Interferon gama/imunologia , Interleucina-17/genética , Interleucina-4/genética , Interleucina-4/imunologia , Lectinas Tipo C/metabolismo , Lectinas de Ligação a Manose/metabolismo , Camundongos , Oxazolona , Receptores de Citocinas/metabolismo , Transdução de Sinais , Pele/patologia , Linfócitos T/metabolismo , Transcriptoma
12.
Reprod Biol Endocrinol ; 19(1): 171, 2021 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-34836513

RESUMO

BACKGROUND: With the increased use of assisted reproductive technology (ART), assessing the potential health risks of children conceived on ART important to public health. Most research in this area has focused on the effects of ART on perinatal, metabolic, and oncological risks in children. Although an increased risk of immune-related diseases has been reported in children born after ART, there are no studies on the immunological status of these children. This study aimed to evaluate the impact of different embryo transfer methods and fertilization strategies on the immune status of the offspring. METHODS: A total of 69 children born to women treated with ART and a matched control group of 17 naturally conceived (NC) children, all aged from 3 to 6 years, were recruited in the reproductive hospital affiliated to Shandong University. The frequency of immune cells in the peripheral blood was assayed using flow cytometry; plasma cytokine levels were determined by multiplex cytokine immunoassay with human cytokine magnetic beads. RESULTS: Compared to children born after natural conception, children born after ART had elevated interferon-γ (IFN-γ) levels, regardless of embryo transfer and fertilization strategies. Children in the fresh-embryo transfer group had significantly higher IL-4 levels and a lower ratio of IFN-γ to IL-4 than those in the NC group ((P = 0.004, 10.41 ± 5.76 pg/mL vs 18.40 ± 7.01 pg/mL, P = 0.023, 1.00 ± 0.48 vs 0.67 ± 0.32, respectively). Similar results were shown in either the in vitro fertilization (IVF) group or the intra-cytoplasmic sperm injection (ICSI) group (P < 0.05 and P = 0.08 for IVF; P < 0.05 and P < 0.05 for ICSI, respectively). These alterations in IL-4 concentrations and the ratio of IFN-γ to IL-4 were statistically significantly correlated with supra-physical E2 (estradiol) levels on the day of hCG administration (R = 0.502, P = 0.017; R = - 0.537, P = 0.010, respectively). Consistently, the frozen embryo transfer did not result in alterations of these immune indicators in the offspring. Overall, there were no significant differences between the ART group and NC group in the frequencies of T cells, B cells, natural killer (NK) cells, CD4+T cells, CD8+T cells, T helper (TH)1 cells, TH17 cells, and regulatory T (Treg) cells and cytokine levels of IL-10 and IL-17a (all P > 0.05). CONCLUSIONS: Immunological alterations existed in children born after the use of ART. The elevated E2 levels before embryo implantation contributed to the increased IL-4 levels in children conceived by fresh embryo transfer. The assessment of immunological alteration is of importance to children conceived by ART for early monitoring and intervention.


Assuntos
Fertilização/imunologia , Interferon gama/imunologia , Interleucina-4/imunologia , Técnicas de Reprodução Assistida/tendências , Criança , Pré-Escolar , Feminino , Fertilização In Vitro/efeitos adversos , Fertilização In Vitro/tendências , Humanos , Masculino , Gravidez , Técnicas de Reprodução Assistida/efeitos adversos , Estudos Retrospectivos
13.
PLoS Negl Trop Dis ; 15(11): e0009886, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34727121

RESUMO

Homeostatic perturbation caused by infection fosters two major defense strategies, resistance and tolerance, which promote the host's survival. Resistance relates to the ability of the host to restrict the pathogen load. Tolerance minimizes collateral tissue damage without directly affecting pathogen fitness. These concepts have been explored mechanistically in murine models of malaria but only superficially in human disease. Indeed, individuals infected with Plasmodium vivax may present with asymptomatic malaria, only mild symptoms, or be severely ill. We and others have reported a diverse repertoire of immunopathological events that potentially underly susceptibility to disease severity in vivax malaria. Nevertheless, the combined epidemiologic, clinical, parasitological, and immunologic features associated with defining the disease outcomes are still not fully understood. In the present study, we perform an extensive outlining of cytokines and inflammatory proteins in plasma samples from a cohort of individuals from the Brazilian Amazon infected with P. vivax and presenting with asymptomatic (n = 108) or symptomatic (n = 134) disease (106 with mild presentation and 28 with severe malaria), as well as from uninfected endemic controls (n = 128) to elucidate these gaps further. We employ highly multidimensional Systems Immunology analyses using the molecular degree of perturbation to reveal nuances of a unique profile of systemic inflammation and imbalanced immune activation directly linked to disease severity as well as with other clinical and epidemiologic characteristics. Additionally, our findings reveal that the main factor associated with severe cases of P. vivax infection was the number of symptoms, despite of a lower global inflammatory perturbation and parasitemia. In these participants, the number of symptoms directly correlated with perturbation of markers of inflammation and tissue damage. On the other hand, the main factor associated with non-severe infections was the parasitemia values, that correlated only with perturbation of inflammatory markers, such as IL-4 and IL-1ß, with a relatively lower number of symptoms. These observations suggest that some persons present severe vivax regardless of pathogen burden and global inflammatory perturbation. Such patients are thus little tolerant to P. vivax infection and show higher susceptibility to disrupt homeostasis and consequently exhibit more clinical manifestations. Other persons are capable to tolerate higher parasitemia with lower inflammatory perturbation and fewer symptoms, developing non-severe malaria. The analytical approach presented here has capability to define in more details the determinants of disease tolerance in vivax malaria.


Assuntos
Malária Vivax/imunologia , Plasmodium vivax/fisiologia , Adulto , Brasil , Feminino , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Malária Vivax/genética , Malária Vivax/parasitologia , Masculino , Pessoa de Meia-Idade , Plasmodium vivax/genética , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto Jovem
14.
Theranostics ; 11(20): 9805-9820, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34815787

RESUMO

Background: Microglia and macrophages adopt a pro-inflammatory phenotype after spinal cord injury (SCI), what is thought to contribute to secondary tissue degeneration. We previously reported that this is due, in part, to the low levels of anti-inflammatory cytokines, such as IL-4. Since IL-13 and IL-4 share receptors and both cytokines drive microglia and macrophages towards an anti-inflammatory phenotype in vitro, here we studied whether administration of IL-13 and IL-4 after SCI leads to beneficial effects. Methods: We injected mice with recombinant IL-13 or IL-4 at 48 h after SCI and assessed their effects on microglia and macrophage phenotype and functional outcomes. We also performed RNA sequencing analysis of macrophages and microglia sorted from the injured spinal cords of mice treated with IL-13 or IL-4 and evaluated the metabolic state of these cells by using Seahorse technology. Results: We observed that IL-13 induced the expression of anti-inflammatory markers in microglia and macrophages after SCI but, in contrast to IL-4, it failed to mediate functional recovery. We found that these two cytokines induced different gene signatures in microglia and macrophages after SCI and that IL-4, in contrast to IL-13, shifted microglia and macrophage metabolism from glycolytic to oxidative phosphorylation. These findings were further confirmed by measuring the metabolic profile of these cells. Importantly, we also revealed that macrophages stimulated with IL-4 or IL-13 are not deleterious to neurons, but they become cytotoxic when oxidative metabolism is blocked. This suggests that the metabolic shift, from glycolysis to oxidative phosphorylation, is required to minimize the cytotoxic responses of microglia and macrophages. Conclusions: These results reveal that the metabolic fitness of microglia and macrophages after SCI contributes to secondary damage and that strategies aimed at boosting oxidative phosphorylation might be a novel approach to minimize the deleterious actions of microglia and macrophages in neurotrauma.


Assuntos
Interleucina-13/metabolismo , Interleucina-4/metabolismo , Traumatismos da Medula Espinal/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Interleucina-13/imunologia , Interleucina-13/farmacologia , Interleucina-4/imunologia , Interleucina-4/farmacologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Recuperação de Função Fisiológica/fisiologia , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/fisiopatologia , Resultado do Tratamento
15.
Int J Mol Sci ; 22(21)2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34769080

RESUMO

The chemokine CCL18 is produced in cells of the myelomonocytic lineage and represents one of the most highly expressed chemokines in lesional skin and serum of atopic dermatitis patients. We investigated the role of histamine in CCL18 production in human monocyte-derived M2 macrophages differentiated in the presence of M-CSF and activated with IL-4, IL-13 or with IL-10. Since expression and regulation of histamine H1 receptor (H1R), H2R and H4R by IL-4 and IL-13 on human M2 macrophages were described, we analyzed expression of the histamine receptors in response to IL-10 stimulation by quantitative RT-PCR. IL-10 upregulated H2R and downregulated H4R mRNA expression by trend in M2 macrophages. IL-10, but in a more pronounced manner, IL-4 and IL-13, also upregulated CCL18. Histamine increased the cytokine-induced upregulation of CCL18 mRNA expression by stimulating the H2R. This effect was stronger in IL-10-stimulated M2 macrophages where the upregulation of CCL18 was confirmed at the protein level by ELISA using selective histamine receptor agonist and antagonists. The histamine-induced CCL18 upregulation in IL-10-activated M2 macrophages was almost similar in cells obtained from atopic dermatitis patients compared to cells from healthy control persons. In summary, our data stress a new function of histamine showing upregulation of the Th2 cells attracting chemokine CCL18 in human, activated M2 macrophages. This may have an impact on the course of atopic dermatitis and for the development of new therapeutic interventions.


Assuntos
Quimiocinas CC/genética , Histamina/imunologia , Macrófagos/imunologia , Células Cultivadas , Quimiocinas CC/imunologia , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Humanos , Inflamação/imunologia , Interleucina-10/imunologia , Interleucina-13/imunologia , Interleucina-4/imunologia , Ativação de Macrófagos , Macrófagos/citologia , Células Th2/imunologia , Regulação para Cima
16.
Front Immunol ; 12: 744738, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34691050

RESUMO

The murine interleukin-4 treated macrophage (MIL4) exerts anti-inflammatory and pro-healing effects and has been shown to reduce the severity of chemical-induced colitis. Positing M(IL4) transfer as an anti-inflammatory therapy, the possibility of side-effects must be considered. Consequently, bone marrow-derived M(IL4)s were administered via intraperitoneal injection to mice concomitant with Citrobacter rodentium infection (infections colitis), azoxymethane/dextran sodium sulphate (AOM/DSS) treatment [a model of colorectal cancer (CRC)], or ovalbumin sensitization (airway inflammation). The impact of M(IL4) treatment on C. rodentium infectivity, colon histopathology, tumor number and size and tissue-specific inflammation was examined in these models. The anti-colitic effect of the M(IL4)s were confirmed in the di-nitrobenzene sulphonic acid model of colitis and the lumen-to-blood movement of 4kDa FITC-dextran and bacterial translocation to the spleen and liver was also improved by M(IL4) treatment. Analysis of the other models of disease, that represent comorbidities that can occur in human inflammatory bowel disease (IBD), revealed that M(IL4) treatment did not exaggerate the severity of any of the conditions. Rather, there was reduction in the size (but not number) of polyps in the colon of AOM/DSS-mice and reduced infectivity and inflammation in C. rodentium-infected mice in M(IL4)-treated mice. Thus, while any new therapy can have unforeseen side effects, our data confirm and extend the anti-colitic capacity of murine M(IL4)s and indicate that systemic delivery of one million M(IL4)s did not exaggerate disease in models of colonic or airways inflammation or colonic tumorigenesis.


Assuntos
Colite/patologia , Neoplasias do Colo/patologia , Interleucina-4/imunologia , Macrófagos/transplante , Hipersensibilidade Respiratória/patologia , Animais , Inflamação/patologia , Macrófagos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL
17.
Int Immunol ; 33(12): 717-722, 2021 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-34628505

RESUMO

IL-4 is known to be the quintessential regulatory cytokine, playing a role in a vast number of immune and non-immune functions. This cytokine is commonly secreted by type 2 helper T (TH2) cells and follicular helper T (TFH) cells after antigenic sensitization. TH2 cells have been classically thought to be the major contributor to B-cell help as a source of IL-4 responsible for class-switch recombination to IgG1 in mice (IgG4 in humans) and to IgE in mice and humans. Recent in vivo observations have shown that IgE and IgG1 antibody responses are mainly controlled by IL-4-secreting TFH cells but not by classical TH2 cells. IL-4 is distinctively regulated in these two T-cell subsets by the GATA-3-mediated HS2 enhancer in TH2 cells and the Notch-mediated conserved non-coding sequence 2 (CNS-2) enhancer in TFH cells. Moreover, the IL-4 derived from TFH cells has an essential role in germinal center (GC) formation in the secondary lymphoid organs during humoral immune responses.


Assuntos
Interleucina-4/imunologia , Células T Auxiliares Foliculares/imunologia , Células Th2/imunologia , Animais , Humanos
18.
Int Immunopharmacol ; 101(Pt A): 108184, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34601334

RESUMO

Trichinellosis is a foodborne zoonosis caused by Trichinella spiralis (T. spiralis) that not only causes considerable economic losses for the global pig breeding and food industries, but also seriously threats the health of human. Therefore, it is very necessary to develop an effective vaccine to prevent trichinellosis. In this study, the invasive Lactobacillus plantarum (L. plantarum) expressing fibronectin-binding protein A (FnBPA) was served as a live bacterial vector to deliver DNA to the host to produce a novel oral DNA vaccine. Co-expressing T. spiralis SS1 and murine interleukin-4 (mIL-4) of DNA vaccine were constructed and subsequently delivered to intestinal epithelial cells via invasive L. plantarum. At 10 days after the third immunization, the experimental mice were challenged with 350 T. spiralis infective larvae. The results found that the mice orally vaccinated with invasive L. plantarum harboring pValac-SS1/pSIP409-FnBPA not only stimulated the production of anti-SS1-specific IgG, Th1/Th2 cell cytokines, and secreted(s) IgA but also decreased worm burden and intestinal damage. However, the mice inoculated with invasive L. plantarum co-expressing SS1 and mIL-4 (pValac-SS1-IL-4/pSIP409-FnBPA) induced the highest protective immune response against T. spiralis infection. The DNA vaccine delivered by invasive L. plantarum provides a novel idea for the prevention of T. spiralis infection.


Assuntos
Vacinas Bacterianas/uso terapêutico , Endodesoxirribonucleases/genética , Proteínas de Helminto/genética , Interleucina-4/genética , Lactobacillus plantarum/imunologia , Trichinella spiralis/imunologia , Triquinelose/prevenção & controle , Administração Oral , Animais , Western Blotting , Endodesoxirribonucleases/imunologia , Imunofluorescência , Proteínas de Helminto/imunologia , Interleucina-4/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Triquinelose/imunologia , Vacinas Sintéticas/uso terapêutico
19.
Nat Commun ; 12(1): 5947, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34642338

RESUMO

Systemic sclerosis (SSc) is a chronic multisystem disorder characterized by fibrosis and autoimmunity. Interleukin (IL)-31 has been implicated in fibrosis and T helper (Th) 2 immune responses, both of which are characteristics of SSc. The exact role of IL-31 in SSc pathogenesis is unclear. Here we show the overexpression of IL-31 and IL-31 receptor A (IL-31RA) in dermal fibroblasts (DFs) from SSc patients. We elucidate the dual role of IL-31 in SSc, where IL-31 directly promotes collagen production in DFs and indirectly enhances Th2 immune responses by increasing pro-Th2 cytokine expression in DFs. Furthermore, blockade of IL-31 with anti-IL-31RA antibody significantly ameliorates fibrosis and Th2 polarization in a mouse model of SSc. Therefore, in addition to defining IL-31 as a mediator of fibrosis and Th2 immune responses in SSc, our study provides a rationale for targeting the IL-31/IL-31RA axis in the treatment of SSc.


Assuntos
Fibroblastos/imunologia , Interleucinas/genética , Receptores de Interleucina/genética , Escleroderma Sistêmico/imunologia , Células Th2/imunologia , Adulto , Idoso , Animais , Anticorpos Monoclonais/farmacologia , Colágeno Tipo I/genética , Colágeno Tipo I/imunologia , Modelos Animais de Doenças , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/patologia , Fibrose , Regulação da Expressão Gênica , Humanos , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Interleucinas/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Isoformas de Proteínas/genética , Isoformas de Proteínas/imunologia , Receptores de Interleucina/antagonistas & inibidores , Receptores de Interleucina/imunologia , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/imunologia , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/patologia , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , Células Th2/efeitos dos fármacos , Células Th2/patologia
20.
Immunity ; 54(10): 2256-2272.e6, 2021 10 12.
Artigo em Inglês | MEDLINE | ID: mdl-34555336

RESUMO

B cells within germinal centers (GCs) enter cycles of antibody affinity maturation or exit the GC as memory cells or plasma cells. Here, we examined the contribution of interleukin (IL)-4 on B cell fate decisions in the GC. Single-cell RNA-sequencing identified a subset of light zone GC B cells expressing high IL-4 receptor-a (IL4Ra) and CD23 and lacking a Myc-associated signature. These cells could differentiate into pre-memory cells. B cell-specific deletion of IL4Ra or STAT6 favored the pre-memory cell trajectory, and provision of exogenous IL-4 in a wild-type context reduced pre-memory cell frequencies. IL-4 acted during antigen-specific interactions but also influenced bystander cells. Deletion of IL4Ra from follicular dendritic cells (FDCs) increased the availability of IL-4 in the GC, impaired the selection of affinity-matured B cells, and reduced memory cell generation. We propose that GC FDCs establish a niche that limits bystander IL-4 activity, focusing IL-4 action on B cells undergoing selection and enhancing memory cell differentiation.


Assuntos
Linfócitos B/imunologia , Diferenciação Celular/imunologia , Células Dendríticas Foliculares/imunologia , Centro Germinativo/imunologia , Memória Imunológica/imunologia , Interleucina-4/imunologia , Animais , Subpopulações de Linfócitos B/imunologia , Camundongos
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