Mitogen-activated protein kinase (MAPK) phosphatases are dual-specificity phosphatases (DUSPs) that dephosphorylate phosphothreonine and phosphotyrosine residues within MAPKs. DUSP6 preferentially dephosphorylates extracellular signal-regulated kinase 1 and 2 (ERK1/2) rendering them inactive. Here, we study the role of DUSP6 in CD4+ T cell function, differentiation, and inflammatory profile in the colon. Upon T cell receptor (TCR) stimulation, DUSP6 knock out (Dusp6−/−) CD4+ T cells showed increased ERK1/2 activation, proliferation, T helper 1 differentiation and IFN-γ production, as well as a marked decrease in survival, IL-17A secretion, and regulatory T cell function. To analyze the role of DUSP6 in vivo, we employed the Il10−/− model of colitis and generated Il10−/−/Dusp6−/− double knockout mice. Il10−/−/Dusp6−/− mice suffered from accelerated and exacerbated spontaneous colitis, which was prevented by ERK1/2 inhibition. ERK1/2 inhibition also augmented regulatory T cell differentiation in vitro and in vivo in both C57Bl/6 and Dusp6−/−mice. In summary, DUSP6 regulates CD4+ T cell activation and differentiation by inhibiting the TCR-dependent ERK1/2 activation. DUSP6 might therefore be a potential intervention target for limiting aberrant T cell responses in T cell mediated diseases such as inflammatory bowel disease.

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Chronic liver inflammation is crucial in the pathogenesis of hepatocellular carcinoma (HCC). Activation of the inflammasome complex is a key inflammatory process that has been associated with different liver diseases, but its role in HCC development remains largely unexplored. Here we analyzed the impact of different inflammasome components, including absent in melanoma 2 (AIM2) and NOD-like receptor family pyrin domain containing 3 (NLRP3), in the development of diethylnitrosamine (DEN)-induced HCC in mice. Genetic inactivation of AIM2, but not NLRP3, reduces liver damage and HCC development in this model. AIM2 deficiency ameliorates inflammasome activation, liver inflammation and proliferative responses during HCC initiation. We also identified that AIM2 is highly expressed in Kupffer cells, and that AIM2-mediated production of IL-1β by these cells is enhanced after DEN-induced liver damage. Our data indicate that AIM2 promotes inflammation during carcinogenic liver injury and that it contributes to genotoxic HCC development in mice, thereby recognizing AIM2 as a potential therapeutic target in this disease.