A20-binding inhibitor of NF-κB (ABIN) 2 negatively regulates allergic airway inflammation

Abstract

TPL-2 MAP 3-kinase promotes inflammation in numerous mouse disease models and is an attractive anti-inflammatory drug target. However, TPL-2–deficient (Map3k8−/−) mice develop exacerbated allergic airway inflammation to house dust mite (HDM) compared with wild type controls. Here, we show that Map3k8D270A/D270A mice expressing kinase dead TPL-2 had an unaltered response to HDM, indicating that the severe airway inflammation observed in Map3k8−/− mice is not due to blockade of TPL-2 signaling and rather reflects a TPL-2 adaptor function. Severe allergic inflammation in TPL-2–deficient mice was likely due to reduced levels of ABIN-2 (TNIP2), whose stability depends on TPL-2 expression. Tnip2E256K knock-in mutation, which reduced ABIN-2 binding to A20, augmented the HDM-induced airway inflammation, but did not affect TPL-2 expression or signaling. These results identify ABIN-2 as a novel negative regulator of allergic airway responses and importantly indicate that TPL-2 inhibitors would not have unwanted allergic comorbidities.

Tumor progression locus 2 (TPL2) in tumor-promoting Inflammation, Tumorigenesis and Tumor Immunity

“…Although the mechanism in which ABIN2 modulates intestinal inflammation is not yet understood, it is plausible that its anti-inflammatory role involves its interaction with A20 and its regulation of NF-κB activation. Consistently, ABIN2 knock-in mutation that impairs ABIN2 interaction with A20 was shown to augment house dust mite (HDM)-mediated allergic airway inflammation, a phenotype similar to that reported in TPL-2 deficient mice 113 , 114 . It is therefore proposed that increased inflammation in TPL2 deficient mice is a result of impaired ABIN2-A20 interaction and signaling.…”

“…Lung tumorigenesis in these mice can be rescued through the reconstitution of either the NF-κB1 p105 or TPL2 protein, suggesting that these proteins are required for the suppression of inflammation and tumorigenesis 43 . Since altered NF-κB1 p105 and TPL2 protein expression can lead to the suppression or expression of ABIN2, the increased tumorigenesis in NF-κB1 p105 or TPL2 deficient mice might be due to loss of ABIN2 protein 108 , 113 , 117 . Moreover, mutations and epigenetic mechanisms that target NF-κB1 p105 and TPL2 expressions such as K-Ras mutation, frequency of LOH on the TPL2 locus and miR-370, can potentially regulate ABIN2 and NF-κB signaling, subsequently promoting inflammation and tumorigenesis 41 , 113 .…”

“…Since altered NF-κB1 p105 and TPL2 protein expression can lead to the suppression or expression of ABIN2, the increased tumorigenesis in NF-κB1 p105 or TPL2 deficient mice might be due to loss of ABIN2 protein 108 , 113 , 117 . Moreover, mutations and epigenetic mechanisms that target NF-κB1 p105 and TPL2 expressions such as K-Ras mutation, frequency of LOH on the TPL2 locus and miR-370, can potentially regulate ABIN2 and NF-κB signaling, subsequently promoting inflammation and tumorigenesis 41 , 113 . In addition, impaired ABIN2 signaling might also contribute to c-Met signaling in TPL2 deficient mice through the activation of NF-κB, thereby creating a feedforward loop that promotes tumor progression and metastasis 113 , 118 , 119 .…”

“…Moreover, mutations and epigenetic mechanisms that target NF-κB1 p105 and TPL2 expressions such as K-Ras mutation, frequency of LOH on the TPL2 locus and miR-370, can potentially regulate ABIN2 and NF-κB signaling, subsequently promoting inflammation and tumorigenesis 41 , 113 . In addition, impaired ABIN2 signaling might also contribute to c-Met signaling in TPL2 deficient mice through the activation of NF-κB, thereby creating a feedforward loop that promotes tumor progression and metastasis 113 , 118 , 119 . Future studies should focus on elucidating the role of ABIN2 signaling in TPL2-mediated tumorigenesis.…”

Epigenetic regulation of epithelial dectin-1 through an IL-33-STAT3 axis in allergic disease

“…In susceptible individuals, it is thought that a insufficiency in these protective mechanisms can drive disease upon exposure to sources of allergens. Several molecular pathways, including pattern recognition receptors like CLEC10A, TLR2, TLR7/8, and TLR9, as well as well-known anti-inflammatory intracellular mediators like A20, have been shown to be protective in asthma [1][2][3][4] . Some of these pathways are epithellial-expressed and their activity can be decreased in allergic patients 2,5 .…”