Reference

J Allergy Clin Immunol. In Press.Cover JACI

Authors

Vento-Tormo R*, Álvarez-Errico D*, Garcia-Gomez A, Hernández-Rodríguez J, Buján S, Basagaña M, Méndez M, Yagüe J, Juan M, Aróstegui JI, Ballestar E. *These authors contributed equally to this work

Abstract

BACKGROUND:
Inflammasomes are cytosolic multiprotein complexes in macrophages. They assemble after infection- or stress-associated stimuli, activating both caspase-1-mediated inflammatory cytokine secretion and pyroptosis. Increased inflammasome activity resulting from gene mutations is related to monogenic autoinflammatory syndromes. However, variable penetrance among patients with the same gene mutations suggests involvement of additional mechanisms associated with inflammasome gene regulation.
OBJECTIVE:
We sought to investigate the role of DNA demethylation in activating inflammasome genes during macrophage differentiation and monocyte activation in healthy control subjects and patients with autoinflammatory syndrome.
METHODS:
Inflammasome-related genes were tested for DNA methylation and mRNA levels by using bisulfite pyrosequencing and quantitative RT-PCR in monocytes in vitro differentiated to macrophages and exposed to inflammatory conditions. The contribution of Tet methylcytosine dioxygenase 2 (TET2) and nuclear factor κB to DNA demethylation was tested by using chromatin immunoprecipitation, small interfering RNA-mediated downregulation, and pharmacologic inhibition.
RESULTS:
We observed that inflammasome-related genes are rapidly demethylated in both monocyte-to-macrophage differentiation and on monocyte activation. Demethylation associates with increased gene expression, and both mechanisms are impaired when TET2 and nuclear factor κB are downregulated. We analyzed DNA methylation levels of inflammasome-related genes in patients with cryopyrin-associated periodic syndromes (CAPS) and familial Mediterranean fever, 2 archetypical monogenic autoinflammatory syndromes. Under the above conditions, monocytes from untreated patients with CAPS undergo more efficient DNA demethylation than those of healthy subjects. Interestingly, patients with CAPS treated with anti-IL-1 drugs display methylation levels similar to those of healthy control subjects.
CONCLUSION:
Our study is the first to demonstrate the involvement of DNA methylation-associated alterations in patients with monogenic autoinflammatory disease and opens up possibilities for novel clinical markers.

Description

Las enfermedades autoinflamatorias se caracterizan por agudos y recurrentes episodios de inflamación, como consecuencia de una desregulación en el proceso inflamatorio. La mayoría de los pacientes presentan mutaciones en genes relacionados con la función y regulación del inflamasoma, aunque existe un grupo de pacientes en los que no se han detectado mutaciones en estos genes, haciendo difícil su diagnóstico. En el presente artículo, hemos identificado por primera vez alteraciones en el proceso de regulación mediada por desmetilación del DNA en los genes del inflamasoma en los monocitos de estos pacientes. Además, hemos determinado que, cuando los pacientes se someten a tratamiento con bloqueadores de IL-1B, estos cambios epigenéticos se revierten, adquiriendo el paciente el perfil de metilación de un individuo control. Todo ello, abre puertas en la búsqueda de nuevos marcadores moleculares, para una mejor identificación y caracterización de estos pacientes, así como su respuesta a distintos tratamientos.

 

Ballestar group 2

 

REFERENCIA DEL GRUPO INVESTIGADOR

El grupo de Cromatina y Enfermedad del Institut d'Investigació Biomèdica de Bellvitge (IDIBELL) está dirigido por el Dr Esteban Ballestar y centra su actividad investigadora en el estudio de mecanismos de desregulación epigenética en el sistema inmune, especialmente en el contexto de enfermedad autoinmune, autoinflamatoria, inmunodeficiencia y en distintos modelos de diferenciación relevantes en enfermedades del sistema inmune. En los últimos años el laboratorio ha publicado diversos trabajos relacionados con la adquisición de alteraciones epigenéticas en distintos tipos celulares relevantes en el contexto inmunológico. http://www.idibell.cat/modul/chromatin-and-disease/en

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