Top Reads

The RNA binding protein AT-rich interaction domain 5a (Arid5a) stabilizes and promotes the translation of IL-17–dependent mRNAs. In this Top Read, Taylor et al. (p. 1138) explored the role of Arid5a in IL-17–driven fungal immunity and autoimmunity. The authors showed that mice lacking Arid5a were resistant to experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Furthermore, Arid5a^−/− mice had reduced numbers of IL-17–producing T cells in lymph nodes during EAE when compared with control animals. Surprisingly, Arid5a^−/− mice, like controls, were resistant to oropharyngeal and systemic candidiasis, unlike IL-17–deficient mice. Collectively, these data indicate that Arid5a is required for EAE pathogenesis but does not play an important role in the response to Candida albicans.

In this Top Read, Maeda et al. (p. 1173) demonstrated that TAK1 limits pyroptotic cell death of macrophages and interferes with signaling downstream of the Fas death receptor. In vitro, macrophages lacking TAK1 were extremely sensitive to FasL and readily underwent cell death characterized by cleaved gasdermin D and E. The authors showed that mice lacking TAK1 in macrophages developed spontaneous tissue inflammation. Mechanistically, TAK1 limited cell death by negatively regulating RIPK1 kinase activity. In vivo, mice lacking TAK1 in macrophages with a catalytically inactive RIPK1 showed reduced spontaneous disease compared with those with a wild-type RIPK1. Collectively, these data provide new insights into the tight regulation of cell death processes in macrophages that prevents autoinflammatory diseases.

After adolescence, females are more likely than males to develop asthma, and the mechanism for this bias is unknown. In this Top Read, Ejima et al. (p. 1083) investigated the impact of sex steroid hormones on airway inflammation using T cell–specific androgen receptor (AR)- and estrogen receptor (ER)-deficient mice. In response to house dust mite (HDM), T cell–specific ER-deficient female mice exhibited similar airway inflammation as control females. However, T cell–specific AR-deficient males developed more severe inflammation than control males. In the lungs, AR-deficient Th2 cells showed increased proliferation and cytokine production, as well as increased cell cycle and Th2-specific gene expression compared with controls. Furthermore, adoptive transfer of OT-II–specific AR-deficient Th2 cells to wild-type mice induced more severe airway inflammation in response to OVA compared with transfer of control Th2 cells. Finally, the authors used chromatin immunoprecipitation of Th2 cells to suggest that AR binds to the 5′ untranslated region of the gene encoding DUSP-2, a negative regulator of p38 MAPK. These data may, in part, explain the sex bias of asthma in humans after adolescence.

In this Top Read, Merchand-Reyes et al. (p. 1212) investigated the differentiation of nurse-like cells (NLCs) to understand how they support chronic lymphocytic leukemia (CLL) growth. CLL patient–derived NLCs showed significant hypomethylation in the binding sites for the transcription factors activator protein-1 (AP-1) and musculoaponeurotic fibrosarcoma (MAF), consistent with the observation that MEK/ERK signaling was high in NLCs. Pharmacological inhibition showed that the MEK/ERK pathway is critical for NLC differentiation but not for NLC survival. The authors also observed increased MEK/ERK activity in the spleens of the Eμ-TCL1 mouse model of CLL. Treatment of these mice with the highly selective MEK inhibitor trametinib slowed disease progression and increased survival time. Trametinib reduced the total of M1- or M2-polarized macrophage numbers and reversed CLL-like morphology in the spleen by affecting B and CLL cell distribution. Altogether, the data demonstrate the dependence of CLL on NLC differentiation and suggest that the FDA-approved drug trametinib may be leveraged for the treatment of CLL.