RESUMO
BACKGROUND: The cytokine TSLP promotes type 2 immune responses and can induce adipose loss by stimulating lipid loss from the skin through sebum secretion by sebaceous glands, which enhances the skin barrier. However, the mechanism by which TSLP upregulates sebaceous gland function is unknown. OBJECTIVES: This study investigated the mechanism by which TSLP stimulates sebum secretion and adipose loss. METHODS: RNA-sequencing analysis was performed on sebaceous glands isolated by laser capture microdissection and single-cell RNA-sequencing analysis was performed on sorted skin T cells. Sebocyte function was analyzed by histological analysis and sebum secretion in vivo and by measuring lipogenesis and proliferation in vitro. RESULTS: This study found that TSLP sequentially stimulated the expression of lipogenesis genes followed by cell death genes in sebaceous glands to induce holocrine secretion of sebum. TSLP did not affect sebaceous gland activity directly. Rather, single-cell RNA-sequencing revealed that TSLP recruited distinct T-cell clusters that produce IL-4 and IL-13, which were necessary for TSLP-induced adipose loss and sebum secretion. Moreover, IL-13 was sufficient to cause sebum secretion and adipose loss in vivo and to induce lipogenesis and proliferation of a human sebocyte cell line in vitro. CONCLUSIONS: This study proposes that TSLP stimulates T cells to deliver IL-4 and IL-13 to sebaceous glands, which enhances sebaceous gland function, turnover, and subsequent adipose loss.
Assuntos
Citocinas , Interleucina-13 , Interleucina-4 , Glândulas Sebáceas , Sebo , Linfócitos T , Linfopoietina do Estroma do Timo , Citocinas/metabolismo , Sebo/metabolismo , Sebo/imunologia , Interleucina-13/metabolismo , Interleucina-13/imunologia , Interleucina-4/metabolismo , Interleucina-4/imunologia , Animais , Glândulas Sebáceas/imunologia , Glândulas Sebáceas/metabolismo , Linfócitos T/imunologia , Humanos , Camundongos , Tecido Adiposo/imunologia , Tecido Adiposo/metabolismo , Lipogênese/imunologia , Camundongos Endogâmicos C57BLRESUMO
Thymic stromal lymphopoietin (TSLP) is critical in developing allergic responses, including atopic dermatitis (AD). We systematically reviewed the literature to complete a meta-analysis to quantitatively summarize the levels of serum TSLP in AD. The study was prospectively registered in the PROSPERO database (ID = CRD42021242628). The PUBMED, SCOPUS, and Cochrane Library databases were reviewed, and original articles investigating serum TSLP in AD patients were included. Differences in TSLP levels of AD patients and controls were summarized by standardized mean differences (SMD) using a random effects model. Study quality was assessed by applying the NewcastleâOttawa Scale. Fourteen studies, which included 1,032 AD patients and 416 controls, were included. Meta-analysis showed that TSLP levels were significantly higher in the AD group than in the control group (SMD = 2.21, 95% CI 1.37-3.06, p < 0.001). Stratification by geographical region, age, disease severity, TSLP determination method, sample size, and study quality revealed significantly elevated TSLP levels in European AD patients (SMD = 3.48, 95% CI 1.75-5.21, p < 0.0001), adult AD patients (SMD = 4.10, 95% CI 2.00-6.21, p < 0.0001), child AD patients (SMD = 0.83, 95% CI 0.08-1.59, p = 0.031), and all severity groups with AD compared with the control group (mild: SMD = 1.15, 95% CI 0.14-2.16, p = 0.025; moderate: SMD = 2.48, 95% CI 0.33-4.62, p = 0.024; and severe: SMD = 8.28, 95% CI 4.82-11.74, p = 2.72e-6). Noticeably, adults showed higher serum TSLP levels than children with AD, and serum TSL levels increased according to AD severity. In conclusion, our meta-analysis demonstrates that circulating TSLP levels are elevated in patients with AD. Future studies are warranted to further elucidate the sources of heterogeneity.
Assuntos
Dermatite Atópica , Linfopoietina do Estroma do Timo , Adulto , Criança , Humanos , CitocinasRESUMO
Although vitamin D (VD) is known to have multiple effects on the skin and immunity, its effects on atopic dermatitis (AD) severity remain unclear. We investigated whether oral cholecalciferol (VD3) supplementation changes stratum corneum expression of the vitamin D receptor (vdr), and the epidermal alarmins Cathelicidin Antimicrobial Peptide (camp/LL-37) and Thymic Stromal Lymphopoietin (tslp) in children with AD. We conducted an open-label supplementation study with weekly oral VD3 for six weeks in children with AD. Serum 25-hydroxyvitamin D (25OHD), lesional Staphylococcus aureus colonization, and AD severity evaluated by SCORAD index were evaluated before and after supplementation. Tape stripping (TS) was performed on non-lesional and lesional skin to measure mRNA expression of vdr, camp, and tslp through RT-qPCR and LL-37 peptide by ELISA. Twenty-two children with moderate-severe AD received weekly oral VD3 for six weeks. Total serum 25OHD increased from 45.1 ± 23 to 93.5 ± 24.3 nmoL/L (p < 0.0001), while SCORAD decreased from 41.4 ± 13.5 to 31.5 ± 15.8 (p < 0.0001). After treatment, epidermal gene expression of camp increased significantly in non-lesional (p = 0.014) and lesional (p = 0.0007) tape stripping samples, while vdr only increased in lesional skin samples (p < 0.0001). LL-37 peptide increased significantly only in lesional skin samples (p = 0.008). Gene expression of tslp did not change after oral VD3 treatment. In children with AD, oral VD3 supplementation was associated with improved VD status and AD severity, as well as increased VDR and Cathelicidin expression in lesional skin, which provide mechanistic clues on its effects.
Assuntos
Dermatite Atópica , Humanos , Criança , Dermatite Atópica/tratamento farmacológico , Catelicidinas/genética , Catelicidinas/metabolismo , Receptores de Calcitriol/genética , Vitamina D , Epiderme/metabolismo , Citocinas/metabolismo , Linfopoietina do Estroma do TimoRESUMO
Indoor environments contribute significantly to total human exposure to air pollutants, as people spend most of their time indoors. Household air pollution (HAP) resulting from cooking with polluting ("dirty") fuels, which include coal, kerosene, and biomass (wood, charcoal, crop residues, and animal manure) is a global environmental health problem. Indoor pollutants are gases, particulates, toxins, and microorganisms among others, that can have an impact especially on the health of children and adults through a combination of different mechanisms on oxidative stress and gene activation, epigenetic, cellular, and immunological systems. Air pollution is a major risk factor and contributor to morbidity and mortality from major chronic diseases. Children are significantly affected by the impact of the environment due to biological immaturity, prenatal and postnatal lung development. Poor air quality has been related to an increased prevalence of clinical manifestations of allergic asthma and rhinitis. Health professionals should increase their role in managing the exposure of children and adults to air pollution with better methods of care, prevention, and collective action. Interventions to reduce household pollutants may promote health and can be achieved with education, community, and health professional involvement.
RESUMO
The respiratory syncytial virus (RSV) is the most prevalent etiological agent of lower respiratory tract infections and the first cause of hospitalization in infants due to respiratory disease worldwide. However, efforts to develop safe and effective vaccines and antivirals have been challenged by an incomplete understanding of the RSV pathogenesis and the host immune response to RSV infection in the airways. Here, we discuss recent advances in understanding the interaction between RSV and the epithelium to induce pathogenesis in the airways, such as the role of the RSV NS2 protein in the airway epithelium, as well as the events involved in the RSV entry process. In addition, we summarize the cellular factors produced by airway epithelial cells (AECs) in response to RSV infection that lead to the activation of innate and adaptive immune responses, inducing lung inflammation and disease. Further, we discuss the possible contribution of a recently identified cytokine, thymic stromal lymphopoitein (TSLP), in the lung immunopathology caused by RSV.
Assuntos
Infecções por Vírus Respiratório Sincicial/metabolismo , Vírus Sincicial Respiratório Humano/metabolismo , Proteínas Virais/metabolismo , Animais , Interações Hospedeiro-Patógeno , Humanos , Infecções por Vírus Respiratório Sincicial/genética , Infecções por Vírus Respiratório Sincicial/virologia , Vírus Sincicial Respiratório Humano/genética , Sistema Respiratório/metabolismo , Sistema Respiratório/virologia , Proteínas Virais/genéticaRESUMO
Human metapneumovirus (hMPV) is a leading cause of acute respiratory tract infections in children and the elderly. The mechanism by which this virus triggers an inflammatory response still remains unknown. Here, we evaluated whether the thymic stromal lymphopoietin (TSLP) pathway contributes to lung inflammation upon hMPV infection. We found that hMPV infection promotes TSLP expression both in human airway epithelial cells and in the mouse lung. hMPV infection induced lung infiltration of OX40L(+) CD11b(+) DCs. Mice lacking the TSLP receptor deficient mice (tslpr(-/-) ) showed reduced lung inflammation and hMPV replication. These mice displayed a decreased number of neutrophils as well a reduction in levels of thymus and activation-regulated chemokine/CCL17, IL-5, IL-13, and TNF-α in the airways upon hMPV infection. Furthermore, a higher frequency of CD4(+) and CD8(+) T cells was found in tslpr(-/-) mice compared to WT mice, which could contribute to controlling viral spread. Depletion of neutrophils in WT and tslpr(-/-) mice decreased inflammation and hMPV replication. Remarkably, blockage of TSLP or OX40L with specific Abs reduced lung inflammation and viral replication following hMPV challenge in mice. Altogether, these results suggest that activation of the TSLP pathway is pivotal in the development of pulmonary pathology and pulmonary hMPV replication.
Assuntos
Citocinas/metabolismo , Metapneumovirus/fisiologia , Infecções por Paramyxoviridae/metabolismo , Infecções por Paramyxoviridae/virologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Transdução de Sinais , Animais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/farmacologia , Linhagem Celular , Citocinas/genética , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Modelos Animais de Doenças , Células Epiteliais/metabolismo , Células Epiteliais/virologia , Expressão Gênica , Humanos , Interleucina-33 , Interleucina-8/genética , Interleucina-8/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Macrófagos Alveolares/imunologia , Macrófagos Alveolares/metabolismo , Metapneumovirus/efeitos dos fármacos , Camundongos , Neutrófilos/imunologia , Neutrófilos/metabolismo , Ligante OX40/antagonistas & inibidores , Ligante OX40/genética , Ligante OX40/metabolismo , Infecções por Paramyxoviridae/tratamento farmacológico , Infecções por Paramyxoviridae/genética , Infecções por Paramyxoviridae/patologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/genética , Pneumonia Viral/patologia , Receptores de Citocinas/antagonistas & inibidores , Receptores de Citocinas/deficiência , Transdução de Sinais/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Subpopulações de Linfócitos T/patologia , Replicação Viral , Linfopoietina do Estroma do TimoRESUMO
Basophils were discovered by Paul Ehrlich in 1879 and represent the least abundant granulocyte population in mammals. The relative rarity of basophils and their phenotypic similarities with mast cells resulted in this cell lineage being historically overlooked, both clinically and experimentally. However, recent studies in human subjects and murine systems have shown that basophils perform nonredundant effector functions and significantly contribute to the development and progression of TH2 cytokine-mediated inflammation. Although the potential functions of murine and human basophils have provoked some controversy, recent genetic approaches indicate that basophils can migrate into lymphoid tissues and, in some circumstances, cooperate with other immune cells to promote optimal TH2 cytokine responses in vivo. This article provides a brief historical perspective on basophil-related research and discusses recent studies that have identified previously unappreciated molecules and pathways that regulate basophil development, activation, and function in the context of allergic inflammation. Furthermore, we highlight the unique effector functions of basophils and discuss their contributions to the development and pathogenesis of allergic inflammation in human disease. Finally, we discuss the therapeutic potential of targeting basophils in preventing or alleviating the development and progression of allergic inflammation.