RESUMEN
Introduction & Objective: Allergic sensitization is an essential step in the development of allergic airway inflammation to birch pollen (BP); however, this process remains to be fully elucidated. Recent scientific advances have highlighted the importance of the allergen context. In this regard, microbial patterns (PAMPs) present on BP have attracted increasing interest. As these PAMPs are recognized by specialized pattern recognition receptors (PRRs), this study aims at investigating the roles of intracellular PRRs and the inflammasome regulator NLRP3. Methods: We established a physiologically relevant intranasal and adjuvant-free sensitization procedure to study BP-induced systemic and local lung inflammation. Results: Strikingly, BP-sensitized Nlrp3-deficient mice showed significantly lower IgE levels, Th2-associated cytokines, cell infiltration into the lung, mucin production and epithelial thickening than their wild-type counterparts, which appears to be independent of inflammasome formation. Intriguingly, bone-marrow chimera revealed that expression of NLRP3 in the hematopoietic system is required to trigger an allergic response. Conclusion: Overall, this study identifies NLRP3 as an important driver of BP-induced allergic immune responses.
Asunto(s)
Administración Intranasal , Alérgenos , Betula , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR , Polen , Animales , Ratones , Alérgenos/inmunología , Betula/inmunología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Hipersensibilidad/inmunología , Inmunoglobulina E/inmunología , Inflamasomas/metabolismo , Inflamasomas/inmunología , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/inmunología , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Extractos Vegetales/farmacología , Polen/inmunología , Masculino , FemeninoRESUMEN
OBJECTIVE: Efforts to manage non-alcoholic fatty liver disease (NAFLD) are limited by the incomplete understanding of the pathogenic mechanisms and the absence of accurate non-invasive biomarkers. The aim of this study was to identify novel NAFLD therapeutic targets andbiomarkers by conducting liver transcriptomic analysis in patients stratified by the presence of the PNPLA3 I148M genetic risk variant. DESIGN: We sequenced the hepatic transcriptome of 125 obese individuals. 'Severe NAFLD' was defined as the presence of steatohepatitis, NAFLD activity score ≥4 or fibrosis stage ≥2. The circulating levels of the most upregulated transcript, interleukin-32 (IL32), were measured by ELISA. RESULTS: Carriage of the PNPLA3 I148M variant correlated with the two major components of hepatic transcriptome variability and broadly influenced gene expression. In patients with severe NAFLD, there was an upregulation of inflammatory and lipid metabolism pathways. IL32 was the most robustly upregulated gene in the severe NAFLD group (adjusted p=1×10-6), and its expression correlated with steatosis severity, both in I148M variant carriers and non-carriers. In 77 severely obese, and in a replication cohort of 160 individuals evaluated at the hepatology service, circulating IL32 levels were associated with both NAFLD and severe NAFLD independently of aminotransferases (p<0.01 for both). A linear combination of IL32-ALT-AST showed a better performance than ALT-AST alone in NAFLD diagnosis (area under the curve=0.92 vs 0.81, p=5×10-5). CONCLUSION: Hepatic IL32 is overexpressed in NAFLD, correlates with hepatic fat and liver damage, and is detectable in the circulation, where it is independently associated with the presence and severity of NAFLD.
Asunto(s)
Perfilación de la Expresión Génica/métodos , Interleucinas/metabolismo , Lipasa/genética , Hígado/metabolismo , Proteínas de la Membrana/genética , Enfermedad del Hígado Graso no Alcohólico , Adulto , Biomarcadores/metabolismo , Progresión de la Enfermedad , Descubrimiento de Drogas , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Obesidad/metabolismo , Polimorfismo de Nucleótido Simple , Índice de Severidad de la Enfermedad , Regulación hacia ArribaRESUMEN
Nonalcoholic fatty liver disease (NAFLD), the most common liver disorder worldwide, is epidemiologically associated with overweight, insulin resistance features and type 2 diabetes, and can progress to advanced liver fibrosis and hepatocellular carcinoma. Genetic factors play an important role in the development of NAFLD, which is a multifactorial disease. Several common naturally occurring variants modulating lipid and retinol metabolism in hepatocytes predispose to NAFLD development and progression, in particular those in PNPLA3, TM6SF2, MBOAT7, and HSD17B13. In addition, genetic variants that protect hepatic cells from oxidative stress modulate the susceptibility to progressive NAFLD. Although the molecular mechanisms linking these genetic variants with liver disease are not yet fully understood, hepatic fat has emerged as a major driver of the disease, while altered retinol metabolism and mitochondrial oxidative stress play a role in determining the development of advanced NAFLD.