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1.
J Allergy Clin Immunol ; 149(2): 685-697, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-34324892

RESUMEN

BACKGROUND: Mast cells are involved in many distinct pathologic conditions, suggesting that they recognize and respond to various stimuli and thus require a rich repertoire of cell surface proteins. However, mast cell surface proteomes have not been comprehensively characterized. OBJECTIVE: We aimed to further characterize the mast cell surface proteome to obtain a better understanding of how mast cells function in health and disease. METHODS: We enriched for glycosylated surface proteins expressed in mouse bone marrow-derived cultured mast cells (BMCMCs) and identified them using mass spectrometry analysis. The presence of novel surface proteins in mast cells was validated by real-time quantitative PCR and flow cytometry analysis in BMCMCs and peritoneal mast cells (PMCs). We developed a clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene editing approach to disrupt genes of interest in BMCMCs. RESULTS: The glycoprotein enrichment approach resulted in the identification of 1270 proteins in BMCMCs, 378 of which were localized to the plasma membrane. The most common protein classes among plasma membrane proteins were small GTPases, receptors, and transporters. One such cell surface protein was CD98 heavy chain (CD98hc), encoded by the Slc3a2 gene. Slc3a2 gene disruption resulted in a significant reduction in CD98hc expression, adhesion, and proliferation. CONCLUSIONS: Glycoprotein enrichment coupled with mass spectrometry can be used to identify novel surface molecules in mast cells. Moreover, CD98hc plays an important role in mast cell function.


Asunto(s)
Cadena Pesada de la Proteína-1 Reguladora de Fusión/análisis , Mastocitos/química , Proteínas de la Membrana/análisis , Proteoma , Animales , Células Cultivadas , Cadena Pesada de la Proteína-1 Reguladora de Fusión/fisiología , Mastocitos/fisiología , Ratones
2.
J Clin Invest ; 132(20)2022 10 17.
Artículo en Inglés | MEDLINE | ID: mdl-36006736

RESUMEN

Invasive bacterial infections remain a major cause of human morbidity. Group B streptococcus (GBS) are Gram-positive bacteria that cause invasive infections in humans. Here, we show that factor XIIIA-deficient (FXIIIA-deficient) female mice exhibited significantly increased susceptibility to GBS infections. Additionally, female WT mice had increased levels of FXIIIA and were more resistant to GBS infection compared with isogenic male mice. We observed that administration of exogenous FXIIIA to male mice increased host resistance to GBS infection. Conversely, administration of a FXIIIA transglutaminase inhibitor to female mice decreased host resistance to GBS infection. Interestingly, male gonadectomized mice exhibited decreased sensitivity to GBS infection, suggesting a role for gonadal androgens in host susceptibility. FXIIIA promoted GBS entrapment within fibrin clots by crosslinking fibronectin with ScpB, a fibronectin-binding GBS surface protein. Thus, ScpB-deficient GBS exhibited decreased entrapment within fibrin clots in vitro and increased dissemination during systemic infections. Finally, using mice in which FXIIIA expression was depleted in mast cells, we observed that mast cell-derived FXIIIA contributes to host defense against GBS infection. Our studies provide insights into the effects of sexual dimorphism and mast cells on FXIIIA expression and its interactions with GBS adhesins that mediate bacterial dissemination and pathogenesis.


Asunto(s)
Factor XIIIa , Infecciones Estreptocócicas , Andrógenos/metabolismo , Animales , Factor XIIIa/metabolismo , Femenino , Fibrina/metabolismo , Fibronectinas/genética , Fibronectinas/metabolismo , Humanos , Masculino , Mastocitos/metabolismo , Ratones , Infecciones Estreptocócicas/genética , Streptococcus agalactiae/metabolismo , Transglutaminasas/metabolismo
3.
Mucosal Immunol ; 13(4): 584-594, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32103153

RESUMEN

Thymic stromal lymphopoietin (TSLP), an epithelial cell-derived cytokine, exhibits both pro-inflammatory and pro-homeostatic properties depending on the context and tissues in which it is expressed. It remains unknown whether TSLP has a similar dual role in the airways, where TSLP is known to promote allergic inflammation. Here we show that TSLP receptor (TSLPR)-deficient mice (Tslpr-/-) and mice treated with anti-TSLP antibodies exhibited increased airway inflammation and morbidity rates after bleomycin-induced tissue damage. We found that signaling through TSLPR on non-hematopoietic cells was sufficient for TSLP's protective function. Consistent with this finding, we showed that TSLP reduces caspase-1 and caspase-3 activity levels in primary human bronchial epithelial cells treated with bleomycin via Bcl-xL up-regulation. These observations were recapitulated in vivo by observing that Tslpr-/- mice showed reduced Bcl-xL expression that paralleled increased lung caspase-1 and caspase-3 activity levels and IL-1ß concentrations in the bronchial-alveolar lavage fluid. Our studies reveal a novel contribution for TSLP in preventing damage-induced airway inflammation.


Asunto(s)
Apoptosis/efectos de los fármacos , Caspasa 1/metabolismo , Citocinas/farmacología , Sustancias Protectoras/farmacología , Mucosa Respiratoria/efectos de los fármacos , Mucosa Respiratoria/metabolismo , Animales , Apoptosis/genética , Biomarcadores , Bleomicina/efectos adversos , Caspasa 3/metabolismo , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Humanos , Inmunoglobulinas/metabolismo , Inmunohistoquímica , Inflamación/tratamiento farmacológico , Inflamación/etiología , Inflamación/metabolismo , Ratones , Ratones Noqueados , Unión Proteica , Receptores de Citocinas/metabolismo , Mucosa Respiratoria/patología , Enfermedades Respiratorias/tratamiento farmacológico , Enfermedades Respiratorias/etiología , Enfermedades Respiratorias/metabolismo , Transducción de Señal/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Proteína bcl-X/genética , Proteína bcl-X/metabolismo , Linfopoyetina del Estroma Tímico
4.
JCI Insight ; 2(19)2017 10 05.
Artículo en Inglés | MEDLINE | ID: mdl-28978795

RESUMEN

Foxp3+ Tregs possess potent immunosuppressive activity, which is critical for maintaining immune homeostasis and self-tolerance. Defects in Treg development or function result in inadvertent immune activation and autoimmunity. Despite recent advances in Treg biology, we still do not completely understand the molecular and cellular mechanisms governing the development and suppressive function of these cells. Here, we have demonstrated an essential role of the dedicator of cytokinesis 8 (DOCK8), guanine nucleotide exchange factors required for cytoskeleton rearrangement, cell migration, and immune cell survival in controlling Treg fitness and their function. Treg-specific DOCK8 deletion led to spontaneous multiorgan inflammation in mice due to uncontrolled T cell activation and production of proinflammatory cytokines. In addition, we show that DOCK8-deficient Tregs are defective in competitive fitness and in vivo suppressive function. Furthermore, DOCK8 controls IL-2 signaling, crucial for maintenance and competitive fitness of Tregs, via a STAT5-dependent manner. Our study provides potentially novel insights into the essential function of DOCK8 in Tregs and immune regulation, and it explains the autoimmune manifestations associated with DOCK8 deficiency.


Asunto(s)
Factores de Intercambio de Guanina Nucleótido/inmunología , Interleucina-2/inmunología , Linfocitos T Reguladores/inmunología , Animales , Autoinmunidad/inmunología , Factores de Intercambio de Guanina Nucleótido/deficiencia , Tolerancia Inmunológica/inmunología , Inflamación/inmunología , Mediadores de Inflamación/metabolismo , Activación de Linfocitos/inmunología , Ratones Noqueados , Factor de Transcripción STAT5/inmunología , Transducción de Señal/inmunología
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