Summary Obesity and type-2 diabetes are associated with tissue-inflammation and metabolic defects in fat depots. Foxp3+regulatory T(Treg) cells mediate T-cell tolerance, thereby controlling tissue inflammation. However, the molecular underpinnings how environmental stimuli interlink T-cell tolerance with adipose tissue function remain largely unknown. Here, we report that cold exposure or beta3-adrenergic receptor (ADRB3) stimulation induces T-cell tolerance in vitro and in murine and humanized models. Tolerance induction was verified by CD4+T-cell-proteomes revealing higher protein expression of Foxp3 regulatory networks. Specifically, Ragulator-interacting protein C17orf59, which limits mTORC1 activity, was upregulated by either ADRB3-stimulation or cold-exposure, and therefore might enhance Treg induction. By loss and gain-of-function studies, including Treg depletion and transfers in vivo, we demonstrated that a T-cell-specific Stat6/Pten axis links cold-exposure or ADRB3 stimulation with Foxp3+Treg induction and adipose tissue function. Our findings open new avenues in understanding tissue-specific T-cell tolerance and the design of precision concepts toward personalized immune-metabolic health.

Breast cancer metastasizes to bone, visceral organs, and/or brain depending on the subtype, which may involve activation of a host organ-specific signaling network in metastatic cells. To test this possibility, we determined gene expression patterns in MDA-MB-231 cells and its mammary fat pad tumor (TMD-231), lung-metastasis (LMD-231), bone-metastasis (BMD-231), adrenal-metastasis (ADMD-231) and brain-metastasis (231-BR) variants. When gene expression between metastases was compared, 231-BR cells showed the highest gene expression difference followed by ADMD-231, LMD-231, and BMD-231 cells. Neuronal transmembrane proteins SLITRK2, TMEM47, and LYPD1 were specifically overexpressed in 231-BR cells. Pathway-analyses revealed activation of signaling networks that would enable cancer cells to adapt to organs of metastasis such as drug detoxification/oxidative stress response/semaphorin neuronal pathway in 231-BR, Notch/orphan nuclear receptor signals involved in steroidogenesis in ADMD-231, acute phase response in LMD-231, and cytokine/hematopoietic stem cell signaling in BMD-231 cells. Only NF-κB signaling pathway activation was common to all except BMD-231 cells. We confirmed NF-κB activation in 231-BR and in a brain metastatic variant of 4T1 cells (4T1-BR). Dimethylaminoparthenolide inhibited NF-κB activity, LYPD1 expression, and proliferation of 231-BR and 4T1-BR cells. Thus, transcriptome change enabling adaptation to host organs is likely one of the mechanisms associated with organ-specific metastasis and could potentially be targeted therapeutically.

Background Atopic dermatitis (AD) is characterized by intense pruritis and is a common childhood inflammatory disease. Many factors are known to affect AD development, including the pleiotropic cytokine interleukin (IL)-4. Yet, still little is known regarding the direct effects of IL-4 on keratinocyte function. Objective and Methods: In this report, RNA-seq and functional assays were used to define the impact of the allergic environment on primary keratinocyte function and wound repair in mice. Results Acute or chronic stimulation by IL-4 modified expression of over 1000 genes expressed in human keratinocytes that are involved in a broad spectrum of non-overlapping functions. Among the IL-4-induced changes, repression of fibronectin critically impaired the human keratinocyte wounding response. Moreover, in mouse models of spontaneous and induced AD-like lesions there was delayed re-epithelialization. Importantly, topical treatment with fibronectin restored the epidermal repair response. Conclusion Keratinocyte gene expression is critically shaped by IL-4, altering cell fate decisions likely important for the clinical manifestations and pathology of allergic skin disease.

Atopic dermatitis (AD) is a chronic inflammatory skin disease induced by a complex interaction between susceptibility genes encoding skin barrier components and environmental allergen exposure that results in type 2 cytokine production. Although genetic lesions in either component can be risk factors for disease in patients, whether these pathways interact in the development of AD is not clear. To test this, we mated mice with T-cell specific expression of constitutively active Stat6 (Stat6VT) that spontaneously develop allergic skin inflammation with Flaky tail (Ft) mice that have mutations in Flg and Tmem79 genes that each affect skin barrier function. Our results demonstrate that over 90% of the Stat6VT transgenic mice carrying the Ft alleles (Stat6VTxFt−/−) develop severe atopic dermatitis lesions by 3-5 months of age, compared with only 40% of Stat6VT mice that develop disease by 6-7 months of age. Further, histopathological analysis of skin tissues from Stat6VTxFt−/− mice revealed extensive thickening of the dermis with increased inflammatory infiltrates as compared with Stat6VT mice. Our study suggests that skin barrier defects and altered Th2 responses independently cooperate in the pathogenesis of allergic skin inflammation, similar to effects observed in patients with AD.

Allergic inflammation requires the orchestration of altered gene expression in the target tissue and in the infiltrating immune cells. The transcription factor STAT6 is critical in activating cytokine gene expression and cytokine signaling both in the immune cells and in target tissue cells including airway epithelia, keratinocytes and esophageal epithelial cells. STAT6 is activated by the cytokines IL-4 and IL-13 to mediate the pathogenesis of allergic disorders such as asthma, atopic dermatitis, food allergy and eosinophilic esophagitis (EoE). In this review, we summarize the role of STAT6 in allergic diseases, its interaction with the co-factor PARP14 and the molecular mechanisms by which STAT6 and PARP14 regulate gene transcription.