RESUMO
Frequent itching and incessant scratching are commonly observed in various chronic inflammatory skin conditions, including atopic dermatitis and psoriasis. The persistent and prolonged nature of pruritus can worsen one's quality of life. Keratinocytes (KCs), the predominant cells of the epidermis, have been confirmed to interact with sensory neurons and immune cells and be involved in chronic skin inflammatory diseases associated with pruritus. Initially, KCs and sensory neurons form a unique synapse-like connection within the epidermis, serving as the structural foundation for their interaction. Additionally, several receptors, including toll-like receptors and protease-activated receptor 2, expressed on KCs, become activated in an inflammatory milieu. On the one hand, activated KCs are sources of pro-inflammatory cytokines and neurotrophic factors, such as adenosine triphosphate, thymic stromal lymphopoietin, and nerve growth factor, which directly or indirectly participate in stimulating sensory neurons, thereby contributing to the itch sensations. On the other hand, KCs also function as primary transducers alongside intraepidermal nerve endings, directly initiating pruritic responses. This review summarizes the current literature and highlights the critical role of KCs in the development and persistence of chronic itch in inflammatory skin disorders.
Assuntos
Queratinócitos , Prurido , Humanos , Prurido/etiologia , Prurido/fisiopatologia , Queratinócitos/metabolismo , Doença Crônica , Células Receptoras Sensoriais/metabolismo , Células Receptoras Sensoriais/fisiologia , Dermatite Atópica/complicações , Animais , Citocinas/metabolismo , Psoríase/complicaçõesRESUMO
Metabolic regulation is integral to the proper functioning of innate lymphoid cells, yet the underlying mechanisms remain elusive. Here, we show that disruption of exogenous proline uptake, either through dietary restriction or by deficiency of the proline transporter Slc6a7, in lymphoid tissue inducer (LTi) cells, impairs LTi activation and aggravates dextran sodium sulfate-induced colitis in mice. With an integrative transcriptomic and metabolomic analysis, we profile the metabolic characteristics of various innate lymphoid cell subsets and reveal a notable enrichment of proline metabolism in LTi cells. Mechanistically, defective proline uptake diminishes the generation of reactive oxygen species, previously known to facilitate LTi activation. Additionally, LTi cells deficient in Slc6a7 display downregulation of Cebpb and Kdm6b, resulting in compromised transcriptional and epigenetic regulation of interleukin-22. Furthermore, our study uncovers the therapeutic potential of proline supplementation in alleviating colitis. Therefore, these findings shed light on the role of proline in facilitating LTi activation and ultimately contributing to gut homeostasis.
Assuntos
Colite , Imunidade Inata , Camundongos , Animais , Epigênese Genética , Linfócitos , Tecido Linfoide , Linfócitos T Auxiliares-Indutores , Colite/induzido quimicamente , HomeostaseRESUMO
Anti-programmed death-1 (PD-1) immunotherapy that aims to restore T cell activity in cancer patients frequently leads to immune-related adverse events such as colitis. However, the underlying mechanism is still elusive. Here, we find that Pdcd1-deficient mice exhibit disrupted gut microbiota and aggravated dextran sulfate sodium (DSS)-induced colitis. In addition to T cells, PD-1 is also substantially expressed in colonic lymphoid tissue inducer (LTi) cells. During DSS-induced colitis, LTi cell activation is accompanied by increased PD-1 expression, whereas PD-1 deficiency results in reduced interleukin-22 (IL-22) production by LTi cells and exacerbated inflammation. Mechanistically, activated LTi cells reprogram their metabolism toward carbohydrate metabolism and fatty acid synthesis, while fatty acid oxidation (FAO) is unchanged. However, PD-1 deficiency leads to significantly elevated FAO in LTi cells, which in turn attenuates their activation and IL-22 production. Consistently, FAO suppression efficiently restores IL-22 production in Pdcd1-/- LTi cells. Thus, our study provides unforeseen mechanistic insight into colitis occurrence during anti-PD-1 immunotherapy through LTi cell metabolic reconfiguration.
Assuntos
Colite , Tecido Linfoide , Animais , Colite/induzido quimicamente , Ácidos Graxos , Tecido Linfoide/metabolismo , Camundongos , Linfócitos T Auxiliares-IndutoresRESUMO
Microbiota-host interaction has attracted more and more attentions in recent years. The association between microbiota and host health is largely attributed to its influence on host immune system. Microbial-derived antigens and metabolites play a critical role in shaping the host immune system, including regulating its development, activation, and function. However, during various diseases the microbiota-host communication is frequently found to be disordered. In particular, gut microbiota dysbiosis associated with or led to the occurrence and progression of infectious diseases, autoimmune diseases, metabolic diseases, and neurological diseases. Pathogenic microbes and their metabolites disturb the protective function of immune system, and lead to disordered immune responses that usually correlate with disease exacerbation. In the other hand, the immune system also regulates microbiota composition to keep host homeostasis. Here, we will discuss the current advances of our knowledge about the interactions between microbiota and host immune system during health and diseases.
RESUMO
PURPOSE: To investigate the clinical efficacy and effects of CAD/CAM zirconia all-ceramic crown, cobalt-chromium alloy and silver-palladium alloy porcelain-fused-to-metal crown restorations on periodontal tissues. METHODS: Forty-nine teeth with crowns in 46 patients were randomly assigned into CAD/CAM zirconia all-ceramic crown group, cobalt-chromium alloy porcelain-fused-to-metal crown group and silver-palladium alloy porcelain-fused-to-metal crown group. The amounts of GCF, TNF-α and IL-6 were analyzed before and 12 months after restorations, and the clinical efficacy was evaluated. RESULTS: Comparing the clinical efficacy within 3 groups, indicators such as color match and the status of gums in CAD/CAM zirconia all-ceramic crown group were significantly better than other 2 groups (P<0.05). The amounts of GCF, TNF-α and IL-6 in CAD/CAM zirconia all-ceramic crown group were also significantly better than other 2 groups (P<0.01). CONCLUSIONS: CAD/CAM zirconia all-ceramic crown restoration had better clinical efficacy than cobalt-chromium alloy and silver-palladium alloy porcelain-fused-to-metal crown restorations with no apparently damage to periodontal tissues.
Assuntos
Desenho Assistido por Computador , Porcelana Dentária , Planejamento de Prótese Dentária , Zircônio , Cerâmica , Coroas , Humanos , Resultado do TratamentoRESUMO
DREAM (downstream regulatory element antagonist modulator), Calsenilin and KChIP3 (potassium channel interacting protein 3) belong to the neuronal calcium sensor (NCS) superfamily, which transduces the intracellular calcium signaling into a variety of activities. They are encoded by the same gene locus, but have distinct subcellular locations. DREAM was first found to interact with DRE (downstream regulatory element) site in the vicinity of the promoter of prodynorphin gene to suppress gene transcription. Calcium can disassemble this interaction by binding reversibly to DREAM protein on its four EF-hand motifs. Apart from having calcium dependent DRE site binding, DREAM can also interact with other transcription factors, such as cAMP responsive element binding protein (CREB), CREB-binding protein (CBP) and cAMP responsive element modulator (CREM), by this concerted actions, DREAM extends the gene pool under its control. DREAM is predominantly expressed in central nervous system with its highest level in cerebellum, and accumulating evidence demonstrated that DREAM might play important roles in pain sensitivity. Novel findings have shown that DREAM is also involved in learning and memory processes, Alzheimer's disease and stroke. This mini-review provides a brief introduction of its discovery history and protein structure properties, focusing on the mechanism of DREAM nuclear translocation and gene transcription regulation functions.