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The most common endotype of asthma is type 2–high asthma, which is sometimes driven by adaptive allergen-specific T H 2 lymphocytes that react to allergens presented by dendritic cells (DCs), or sometimes by an innate immune response dominated by type 2 innate lymphocytes (ILC2s). Understanding the underlying pathophysiology of asthma is essential to improve patient-tailored therapy. The STE20 kinase thousand-and-one kinase 3 (TAOK3) controls key features in the biology of DCs and lymphocytes, but to our knowledge, its potential usefulness as a target for asthma therapy has not yet been addressed. We examined if and how loss of Taok3 affects the development of house dust mite (HDM)-driven allergic asthma in an in vivo mouse model. Wild-type Taok3 +/+ and gene-deficient Taok3 −/− mice were sensitized and challenged with HDM, and bronchoalveolar lavage fluid composition, mediastinal lymph node cytokine production, lung histology, and bronchial hyperreactivity measured. Conditional Taok3 fl/fl mice were crossed to tissue- and cell-specific specific deletor Cre mice to understand how Taok3 acted on asthma susceptibility. Kinase-dead (KD) Taok3 KD mice were generated to probe for the druggability of this pathway. Activation of HDM-specific T cells was measured in adoptively transferred HDM-specific T-cell receptor–transgenic CD4+ T cells. ILC2 biology was assessed by in vivo and in vitro IL-33 stimulation assays in Taok3 −/− and Taok3 +/+ , Taok3 KD, and Red5-Cre Taok3 fl/fl mice. Taok3 −/− mice failed to mount salient features of asthma, including airway eosinophilia, T H 2 cytokine production, IgE secretion, airway goblet cell metaplasia, and bronchial hyperreactivity compared to controls. This was due to intrinsic loss of Taok3 in hematopoietic and not epithelial cells. Loss of Taok3 resulted in hampered HDM-induced lung DC migration to the draining lymph nodes and defective priming of HDM-specific T H 2 cells. Strikingly, HDM and IL-33–induced ILC2 proliferation and function were also severely affected in Taok3-deficient and Taok3 KD mice. Absence of Taok3 or loss of its kinase activity protects from HDM-driven allergic asthma as a result of defects in both adaptive DC-mediated T H 2 activation and innate ILC2 function. This identifies Taok3 as an interesting drug target, justifying further testing as a new treatment for type 2–high asthma. [Display omitted] [ABSTRACT FROM AUTHOR]

Obesity-induced inflammation is a major driving force in the development of insulin resistance, type 2 diabetes (T2D), and related metabolic disorders. During obesity, macrophages accumulate in the visceral adipose tissue, creating a low-grade inflammatory environment. Nuclear factor κB (NF-κB) signaling is a central coordinator of inflammatory responses and is tightly regulated by the anti-inflammatory protein A20. Here, we find that myeloid-specific A20-deficient mice are protected from diet-induced obesity and insulin resistance despite an inflammatory environment in their metabolic tissues. Macrophages lacking A20 show impaired mitochondrial respiratory function and metabolize more palmitate both in vitro and in vivo. We hypothesize that A20-deficient macrophages rely more on palmitate oxidation and metabolize the fat present in the diet, resulting in a lean phenotype and protection from metabolic disease. These findings reveal a role for A20 in regulating macrophage immunometabolism. [Display omitted] • Myeloid A20 deficiency creates a pro-inflammatory environment in metabolic tissues • Myeloid A20 deficiency protects mice from diet-induced obesity and insulin resistance • Myeloid A20 deficiency promotes the expansion of inflammatory CD206+ ATMs • A20-deficient macrophages metabolize more palmitate in vitro and in vivo Catrysse et al. show that absence of A20 in myeloid cells leads to protection against diet-induced obesity and insulin resistance. They speculate that this is caused by increased oxygen consumption and increased fatty acid metabolism of A20-deficient macrophages. These findings reveal a role for A20 in regulating macrophage immunometabolism. [ABSTRACT FROM AUTHOR]

Regenerative responses predispose tissues to tumor formation by largely unknown mechanisms. High-mobility group box 1 (HMGB1) is a danger-associated molecular pattern contributing to inflammatory pathologies. We show that HMGB1 derived from keratinocytes, but not myeloid cells, delays cutaneous wound healing and drives tumor formation. In wounds of mice lacking HMGB1 selectively in keratinocytes, a marked reduction in neutrophil extracellular trap (NET) formation is observed. Pharmacological targeting of HMGB1 or NETs prevents skin tumorigenesis and accelerates wound regeneration. HMGB1-dependent NET formation and skin tumorigenesis is orchestrated by tumor necrosis factor (TNF) and requires RIPK1 kinase activity. NETs are present in the microenvironment of keratinocyte-derived tumors in mice and lesional and tumor skin of patients suffering from recessive dystrophic epidermolysis bullosa, a disease in which skin blistering predisposes to tumorigenesis. We conclude that tumorigenicity of the wound microenvironment depends on epithelial-derived HMGB1 regulating NET formation, thereby establishing a mechanism linking reparative inflammation to tumor initiation. • HMGB1 controls transition from pre-cancerous to cancerous lesions in skin • Epithelial HMGB1 promotes neutrophil recruitment and NET formation • TNF and RIPK1 activity mediate HMGB1-dependent NET formation and skin tumorigenesis • NET formation occurs in lesional and tumor-associated skin of RDEB patients Inflammation mediates tissue repair but can be hijacked to promote tumorigenesis. Hoste et al. demonstrate that HMGB1 delays regeneration and drives tumor formation in skin by recruitment and priming of neutrophils. These data indicate that therapies targeting HMGB1 or NET formation might be relevant in chronic and diabetic wound treatment. [ABSTRACT FROM AUTHOR]