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.
Highlights
The MAP-3 Kinase Tumor Progression Locus 2 (TPL-2; known as MAP3K8 and COT) is a key regulator of inflammation
Distinct from Map3k8−/− mice, which developed a severe allergic response to house dust mite (HDM) as expected (Kannan et al, 2016), the response of Map3k8D270A/D270A mice was similar to WT controls (Fig. 1). 1 d after the final oropharyngeal HDM challenge, Map3K8D270A/D270A mice had similar cellular infiltration in bronchoalveolar lavage (BAL) fluid as WT mice (Fig. 1 B)
Tnip2 null mutation phenocopies Map3k8-null mutation in HDM-induced allergy We have previously shown that A20 binding inhibitor of NF-κB 2 (ABIN-2) protein stability is dependent on TPL-2 expression in macrophages (Papoutsopoulou et al, 2006; Sriskantharajah et al, 2014)
Summary
The MAP-3 Kinase Tumor Progression Locus 2 (TPL-2; known as MAP3K8 and COT) is a key regulator of inflammation. Following TLR and TNFR1 stimulation of myeloid cells, TPL-2 phosphorylates and activates MKK1/2 and MKK3/6, leading to the activation of the downstream ERK1/2 and p38α MAP kinases, respectively, and modulation of inflammatory cytokine and chemokine production (Gantke et al, 2011, 2012; Pattison et al, 2016). TPL-2–deficient (Map3k8−/−) mice develop more severe type 2 allergic airway inflammation in response to challenge with ovalbumin or house dust mite (HDM; Watford et al, 2010; Kannan et al, 2016). TPL-2 inhibitors, could have unwanted impacts on allergic comorbidities
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