RESUMO
Intestinal bacteria metabolize dietary substances to produce bioactive postbiotics, among which some are recognized for their role in promoting host health. We here explored the postbiotic potential of two omega-3 α-linolenic acid-derived metabolites: trans-10-cis-15-octadecadienoic acid (t10,c15-18:2) and cis-9-cis-15-octadecadienoic acid (c9,c15-18:2). Dietary intake of lipids rich in omega-3 α-linolenic acid elevated levels of t10,c15-18:2 and c9,c15-18:2 in the serum and feces of mice, an effect dependent on the presence of intestinal bacteria. Notably, t10,c15-18:2 mitigated skin inflammation in mice that became hypersensitive after exposure to 2,4-dinitrofluorobenzene, an experimental model for allergic contact dermatitis. In particular, t10,c15-18:2-but not c9,c15-18:2-attenuated ear swelling and edema, characteristic symptoms of contact hypersensitivity. The anti-inflammatory effects of t10,c15-18:2 were due to its ability to suppress the release of vascular endothelial growth factor A from keratinocytes, thereby mitigating the enhanced vascular permeability induced by hapten stimulation. Our study identified retinoid X receptor as a functional receptor that mediates the downregulation of skin inflammation upon treatment with t10,c15-18:2. Our results suggest that t10,c15-18:2 holds promise as an omega-3 fatty acid-derived postbiotic with potential therapeutic implications for alleviating the skin edema seen in allergic contact dermatitis-induced inflammation.
Assuntos
Modelos Animais de Doenças , Regulação para Baixo , Ácidos Graxos Ômega-3 , Fator A de Crescimento do Endotélio Vascular , Animais , Camundongos , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-3/farmacologia , Dermatite de Contato/metabolismo , Dinitrofluorbenzeno , Pele/metabolismo , Pele/patologia , Queratinócitos/metabolismo , Queratinócitos/efeitos dos fármacos , Feminino , Dermatite Alérgica de Contato/metabolismo , Humanos , Microbioma Gastrointestinal/efeitos dos fármacos , Fezes/química , Fezes/microbiologiaRESUMO
BACKGROUND: Drug-induced interstitial lung disease (DIILD) is a serious adverse event potentially induced by any antineoplastic agent. Whether cancer patients are predisposed to a higher risk of DIILD after receiving immune checkpoint inhibitors (ICIs) is unknown. METHODS: This study retrospectively assessed the cumulative incidence of DIILD in consecutive cancer patients who received post-ICI antineoplastic treatment within 6 months from the final dose of ICIs. There was also a separate control cohort of 55 ICI-naïve patients with non-small cell lung cancer (NSCLC) who received docetaxel. RESULTS: Of 552 patients who received ICIs, 186 met the inclusion criteria. The cohort predominantly comprised patients with cancer of the lung, kidney/urinary tract, or gastrointestinal tract. The cumulative incidence of DIILD in the entire cohort at 3 and 6 months was 4.9% (95% confidence interval [CI] 2.4%-8.7%) and 7.2% (95% CI 4.0%-11.5%), respectively. There were significant differences according to cancer type (Gray's test, P = .04), with the highest cumulative incidence of DIILD in patients with lung cancer being 9.8% (95% CI 4.3%-18.0%) at 3 months and 14.2% (95% CI 7.3%-23.3%) at 6 months. DIILD was caused by docetaxel in six of these 11 lung cancer patients (54.5%). After matching, the cumulative incidence of docetaxel-induced ILD in patients with NSCLC in the post-ICI setting was higher than that in the ICI-naïve setting: 13.0% (95% CI 3.3%-29.7%) vs 4.3% (95% CI 0.3%-18.2%) at 3 months; and 21.7% (95% CI 7.9%-39.9%) vs 4.3% (95% CI 0.3%-18.2%) at 6 months. However, these were not significant differences (hazard ratio, 5.37; 95% CI 0.64-45.33; Fine-Gray P = .12). CONCLUSIONS: Patients with lung cancer were at high risk of developing DIILD in subsequent regimens after ICI treatment. Whether NSCLC patients are predisposed to additional risk of docetaxel-induced ILD by prior ICIs warrants further study.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Doenças Pulmonares Intersticiais , Neoplasias Pulmonares , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Docetaxel/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Estudos Retrospectivos , Neoplasias Pulmonares/tratamento farmacológico , Antineoplásicos/efeitos adversos , Doenças Pulmonares Intersticiais/induzido quimicamente , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/epidemiologiaAssuntos
COVID-19 , Hipo-Hidrose , Humanos , SARS-CoV-2 , COVID-19/prevenção & controle , Vacinação/efeitos adversosRESUMO
BACKGROUND: The integumentary system of the skin serves as an exceptional protective barrier, with the stratum corneum situated at the forefront. This outermost layer is composed of keratinocytes that biosynthesize filaggrin (encoded by the gene Flg), a pivotal constituent in maintaining skin health. Nevertheless, the precise role of sensory nerves in restoration of the skin barrier after tape stripping-induced epidermal disruption, in contrast to the wound-healing process, remains a tantalizing enigma. OBJECTIVE: This study aimed to elucidate the cryptic role of sensory nerves in repair of the epidermal barrier following tape stripping-induced disruption. METHODS: Through the implementation of resiniferatoxin (RTX)-treated denervation mouse model, we investigated the kinetics of barrier repair after tape stripping and performed immunophenotyping and gene expression analysis in the skin or dorsal root ganglia (DRG) to identify potential neuropeptides. Furthermore, we assessed the functional impact of candidates on the recovery of murine keratinocytes and RTX-treated mice. RESULTS: Ablation of TRPV1-positive sensory nerve attenuated skin barrier recovery and sustained subcutaneous inflammation, coupled with elevated IL-6 level in ear homogenates after tape stripping. Expression of the keratinocyte differentiation marker Flg in the ear skin of RTX-treated mice was decreased compared with that in control mice. Through neuropeptide screening, we found that the downregulation of Flg by IL-6 was counteracted by somatostatin or octreotide (a chemically stable somatostatin analog). Furthermore, RTX-treated mice given octreotide exhibited a partial improvement in barrier recovery after tape stripping. CONCLUSION: Sensory neurons expressing TRPV1 play an indispensable role in restoring barrier function following epidermal injury. Our findings suggest the potential involvement of somatostatin in restoring epidermal repair after skin injury.
Assuntos
Interleucina-6 , Neuropeptídeos , Camundongos , Animais , Interleucina-6/metabolismo , Octreotida/metabolismo , Epiderme/metabolismo , Somatostatina/metabolismo , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/metabolismoRESUMO
DiGeorge syndrome, also known as 22q11.2 deletion syndrome, shows cellular immunodeficiency due to by thymic hypoplasia and hypocalcemia caused by hypoparathyroidism. It was reported that erythrodermic psoriasis occurred in a patient with 22q11 deletion syndrome. Here, we report the first case of DiGeorge syndrome presenting with a severe palmoplantar pustulosis (PPP)-like eruption with extra-palmoplantar lesions on the distal limbs. Given that PPP is a subtype of pustular psoriasis, the pustular eruption may be associated with DiGeorge syndrome. We measured serum levels of citrullinated histone H3 (CitH3), a representative marker of neutrophil extracellular traps, interleukin (IL)-8, and IL-22 and compared them with nine cases of typical PPP. In the PPP patients, the three markers were higher than in healthy subjects with significant correlations between CitH3 and IL-8/IL-22. In our patient, CitH3, IL-8, and IL-22 were also high, and IL-22 was remarkably elevated compared with the PPP patients. Our case suggests that a certain T cell abnormality associated with DiGeorge syndrome induces IL-22 overproduction, leading to the PPP-like eruption with extra- palmoplantar lesions.
Assuntos
Síndrome de DiGeorge , Armadilhas Extracelulares , Interleucina 22 , Interleucina-8 , Interleucinas , Psoríase , Humanos , Síndrome de DiGeorge/sangue , Síndrome de DiGeorge/diagnóstico , Síndrome de DiGeorge/imunologia , Síndrome de DiGeorge/complicações , Interleucinas/sangue , Psoríase/sangue , Psoríase/diagnóstico , Psoríase/imunologia , Psoríase/complicações , Interleucina-8/sangue , Masculino , Armadilhas Extracelulares/imunologia , Feminino , Biomarcadores/sangueAssuntos
Psoríase , Humanos , Doença Aguda , Causalidade , Doença Crônica , Psoríase/epidemiologia , Psoríase/genética , Pirina/genéticaRESUMO
Mast cells (MCs) are immune cells residing in tissues and playing indispensable roles in maintaining homeostasis and inflammatory states. Skin lesions associated with atopic dermatitis (AD) and type 2 skin inflammation display an increment in MCs, which have both pro- and anti-inflammatory effects. The direct and indirect activations of skin MCs by environmental factors such as Staphylococcus aureus can instigate type 2 skin inflammation in AD with poorly understood mechanisms. Furthermore, both IgE-dependent and -independent degranulation of MCs contribute to pruritus in AD. Conversely, MCs suppress type 2 skin inflammation by promoting Treg expansion through IL-2 secretion in the spleen. Moreover, skin MCs can upregulate gene expression involved in skin barrier function, thus mitigating AD-like inflammation. These functional variances of MCs in AD could stem from differences in experimental systems, their localization, and origins. In this review, we will focus on how MCs are maintained in the skin under homeostatic and inflammatory conditions, and how they are involved in the pathogenesis of type 2 skin inflammation.
Assuntos
Dermatite Atópica , Mastócitos , Humanos , Imunoglobulina E , Pele/patologia , InflamaçãoAssuntos
Antirreumáticos , Artrite Reumatoide , Azetidinas , Síndrome de Sézary , Neoplasias Cutâneas , Humanos , Síndrome de Sézary/tratamento farmacológico , Artrite Reumatoide/tratamento farmacológico , Azetidinas/efeitos adversos , Neoplasias Cutâneas/tratamento farmacológico , Antirreumáticos/uso terapêutico , Resultado do TratamentoRESUMO
Prostanoids and leukotrienes (LTs) are representative of ω6 fatty acid-derived metabolites that exert their actions through specific receptors on the cell surface. These lipid mediators, being unstable in vivo, act locally at their production sites; thus, their physiological functions remain unclear. However, recent pharmacological and genetic approaches using experimental murine models have provided significant insights into the roles of these lipid mediators in various pathophysiological conditions, including cutaneous inflammatory diseases. These lipid mediators act not only through signaling by themselves but also by potentiating the signaling of other chemical mediators, such as cytokines and chemokines. For instance, prostaglandin E2 -EP4 and LTB4 -BLT1 signaling on cutaneous dendritic cells substantially facilitate their chemokine-induced migration ability into the skin and play critical roles in the priming and/or activation of antigen-specific effector T cells in the skin. In addition to these ω6 fatty acid-derived metabolites, various ω3 fatty acid-derived metabolites regulate skin immune cell functions, and some exert potent anti-inflammatory functions. Lipid mediators act as modulators of cutaneous immune responses, and manipulating the signaling from lipid mediators has the potential as a novel therapeutic approach for human skin diseases.
Assuntos
Dermatite Atópica , Dermatopatias , Humanos , Animais , Camundongos , Prostaglandinas , Pele , Ácidos GraxosRESUMO
Retinol is widely used in topical skincare products to ameliorate skin aging and treat acne and wrinkles; however, retinol and its derivatives occasionally have adverse side effects, including the induction of irritant contact dermatitis. Previously, we reported that mead acid (5,8,11-eicosatrienoic acid), an oleic acid metabolite, ameliorated skin inflammation in dinitrofluorobenzene-induced allergic contact hypersensitivity by inhibiting neutrophil infiltration and leukotriene B4 production by neutrophils. Here, we showed that mead acid also suppresses retinol-induced irritant contact dermatitis. In a murine model, we revealed that mead acid inhibited keratinocyte abnormalities such as keratinocyte hyperproliferation. Consistently, mead acid inhibited p38 MAPK (mitogen-activated protein kinase) phosphorylation, which is an essential signaling pathway in the keratinocyte hyperplasia induced by retinol. These inhibitory effects of mead acid were associated with the prevention of both keratinocyte hyperproliferation and the gene expression of neutrophil chemoattractants, including Cxcl1 and Cxcl2, and they were mediated by a PPAR (peroxisome proliferator-activated receptor)-α pathway. Our findings identified the anti-inflammatory effects of mead acid, the use of which can be expected to minimize the risk of adverse side effects associated with topical retinoid application.
RESUMO
BACKGROUND: Mast cells (MCs) are tissue-resident cells with various immunologic functions. MCs are increased in atopic dermatitis (AD) skin and can contribute to the inflammation. Although skin MCs are inducible from bone marrow (BM) cells in vitro, they are maintained locally by self-proliferation in the steady state in vivo. However, how skin MCs are increased in AD skin, including the infiltration of BM-derived MC progenitors (MCps) and their differentiation, remains unclear. OBJECTIVE: We sought to identify and characterize BM-derived MCps in AD skin. METHODS: BM-derived MCps in AD skin were analyzed by flow cytometry using BM-chimeric mice and parabiosis in an MC903-induced AD model. BM-derived MCps in AD-like skin were compared with resident MCs for gene expression by RNA- sequencing analysis. RESULTS: We observed local proliferation of resident MCs and an increase in BM-derived MCs in AD-like skin. BM-derived MCs in the skin were derived from circulating MCps and were distinguishable from resident MCs by integrinß7. RNA- sequence analysis showed that integrinß7+ MCs (BM-derived MCps) in the skin shared the characteristics of both mucosal-type MCs and connective tissue-type MCs, and increased the expression of genes related to MCp migration. BM-derived MCps proliferated in situ, gradually lost the integrinß7 expression, and acquired connective tissue-type MC phenotypes during the remission phase of inflammation. CONCLUSIONS: BM-derived integrinß7+ MCps migrate to AD-like skin and contribute to the maintenance of skin MCs.
Assuntos
Dermatite Atópica , Camundongos , Animais , Dermatite Atópica/metabolismo , Mastócitos , Medula Óssea/metabolismo , Diferenciação Celular , Inflamação/metabolismo , RNA/metabolismoAssuntos
Melanoma , Penfigoide Bolhoso , Neoplasias Cutâneas , Humanos , Nivolumabe/efeitos adversos , Melanoma/tratamento farmacológico , Melanoma/patologia , Penfigoide Bolhoso/induzido quimicamente , Penfigoide Bolhoso/patologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/patologia , Células Sanguíneas/patologiaRESUMO
Melanoma is a malignant skin tumor with high metastatic activity. Although melanoma has been well-studied, its cellular kinetics remain elusive. The cholecystokinin (CCK) receptor is expressed in various types of tumors because CCK promotes the survival and proliferation of tumor cells. Thus, we hypothesized that the growth of melanoma was positively regulated by signals from the CCK receptor and sought to investigate whether CCK receptor antagonists affect the growth of melanoma cells expressing CCK receptor. Immunohistochemically, the CCK receptor A is expressed in the clinical specimens of melanoma. CCK receptor antagonists decreased the viability of melanoma cells by suppressing cell division and promoting apoptosis. CCK receptor antagonists also decreased the mitochondrial membrane potential through enhanced gene expression of the proapoptotic protein, Bcl2-associated X, and tumor suppressor, p53, suggesting that the antagonist induced the apoptosis of melanoma cells in a mitochondria-dependent manner. In addition, a caspase 3 inhibitor, Z-DEVD-FMK, partially blocked the antiviability of the antagonist, indicating that caspase 3 is involved in antagonist-induced apoptosis. Notably, tumor growth was attenuated when a CCK receptor antagonist was locally administered to the melanoma-bearing mice. Therefore, our study suggests the therapeutic potential of CCK receptor antagonists in the treatment of skin cancer.