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1.
J Allergy Clin Immunol ; 151(3): 791-796.e7, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36462957

RESUMO

BACKGROUND: Toll-like receptors (TLRs) are important pattern recognition receptors that sense microbes and control host defense. Myeloid differentiation protein 2 (MD2) is the indispensable coreceptor for TLR4, facilitating the binding to the gram-negative bacterial cell wall component LPS and activation of downstream signaling. OBJECTIVE: We sought to provide phenotypic and mechanistic insights into human MD2 deficiency. METHODS: To elucidate the genetic cause in a patient with very early onset inflammatory bowel disease, we performed whole-exome sequencing and studied the functional consequences of the identified mutation in LY96 (encoding for MD2) in genetically engineered induced pluripotent stem cell-derived macrophages with knockout of MD2 or knockin of the patient-specific mutation, including TLR4-mediated signaling, cytokine production, and bacterial handling. RESULTS: Whole-exome sequencing identified a homozygous in-frame deletion in the LY96 gene (c.347_349delCAA; p.Thr116del) in a patient with very early onset inflammatory bowel disease and a sibling presenting with pneumonia and otitis media. Induced pluripotent stem cell-derived macrophages with knockout of MD2 or expression of the Thr116del mutation showed impaired activation of nuclear factor kappa B and mitogen-activated protein kinase signaling as well as TLR4 endocytosis on challenge with LPS or bacteria. In addition, MD2-deficient macrophages showed decreased cytokine expression (eg, IL-6, TNF, and IL-10) in response to LPS or gram-negative but not gram-positive bacteria. CONCLUSIONS: Human MD2 deficiency causes defective TLR4 signaling in response to LPS or gram-negative bacteria. The clinical manifestations and expressivity might be variable due to unknown secondary risk factors. Because TLR4 represents a therapeutic target for multiple inflammatory conditions, our study may provide insights into potential side effects of pharmacological TLR4 targeting.


Assuntos
Lipopolissacarídeos , Receptor 4 Toll-Like , Humanos , Citocinas/metabolismo , Lipopolissacarídeos/farmacologia , Antígeno 96 de Linfócito/metabolismo , Transdução de Sinais , Receptor 4 Toll-Like/genética , Receptores Toll-Like/metabolismo
2.
Development ; 143(16): 2907-19, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27385008

RESUMO

Tissue homeostasis relies on the ability of tissues to respond to stress. Tissue regeneration and tumour models in Drosophila have shown that c-Jun amino-terminal kinase (JNK) acts as a prominent stress-response pathway promoting injury-induced apoptosis and compensatory proliferation. A central question remaining unanswered is how both responses are balanced by activation of a single pathway. Signalling through the Janus kinase/Signal transducers and activators of transcription (JAK/STAT) pathway, which is a potential JNK target, is implicated in promoting compensatory proliferation. While we observe JAK/STAT activation in imaginal discs upon damage, our data demonstrate that JAK/STAT and its downstream effector Zfh2 promote the survival of JNK signalling cells. The JNK component fos and the pro-apoptotic gene hid are regulated in a JAK/STAT-dependent manner. This molecular pathway restrains JNK-induced apoptosis and spatial propagation of JNK signalling, thereby limiting the extent of tissue damage, as well as facilitating systemic and proliferative responses to injury. We find that the pro-survival function of JAK/STAT also drives tumour growth under conditions of chronic stress. Our study defines the function of JAK/STAT in tissue stress and illustrates how crosstalk between conserved signalling pathways establishes an intricate equilibrium between proliferation, apoptosis and survival to restore tissue homeostasis.


Assuntos
Proteínas de Drosophila/metabolismo , Drosophila/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Fatores de Transcrição STAT/metabolismo , Animais , Apoptose/genética , Apoptose/fisiologia , Proliferação de Células/genética , Proliferação de Células/fisiologia , Sobrevivência Celular/genética , Sobrevivência Celular/fisiologia , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Drosophila/fisiologia , Proteínas de Drosophila/genética , Proteínas Quinases JNK Ativadas por Mitógeno/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Fosforilação/genética , Fosforilação/fisiologia , Fatores de Transcrição STAT/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia
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