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Abnormal alveolar development and homeostasis are common features of pulmonary disease. Here the authors show that Myh10 expression is reduced in emphysema patients, and that Myh10 loss of function impairs alveolar formation and lung morphogenesis via upregulation of matrix metalloproteinase activity and altered matrix remodeling.

The authors show that activation of free fatty acid receptor 4 on islet macrophages leads to release of interleukin-6, which promotes glucose-stimulated insulin secretion. This mechanism is impaired in obesity-associated type 2 diabetes.

Jin et al. identified PKN1 as the kinase responsible for histone phosphorylation-mediated FOS/FOSB induction and vessel inflammation in regions of disturbed blood flow, highlighting an additional regulation layer for atherosclerotic plaque development.

Lactate is a by-product of glycolysis that can function via its G protein receptor GPR81. Here the authors show that LPS or Salmonella infection enhances glycolytic metabolism in bone marrow neutrophils, resulting in lactate production, which increases endothelial barrier permeability and mobilization of these neutrophils by targeting endothelial GPR81.

Macrophages possess different G protein-coupled receptors such as the orphan receptor GPRC5B. Here the authors characterise the function of GPRC5B in macrophages in knockout mice showing that in the absence of GPRC5B there is increased inflammatory responses and macrophage activation because of reduced EP2-mediated anti-inflammatory effects.

The expansion of the white adipose tissue during obesity is accompanied by increased cellular stress, but factors that protect adipocytes from cell death are not well known. Here the authors report that the transcriptional co-activators YAP and TAZ are activated in adipocytes during obesity, which increases adipocyte survival through the proapoptotic factor BIM.

Authors utilise a murine model of infection to provide mechanistic insight into how antimicrobial therapy may be a predisposing risk factor for hospital-acquired pneumonia. They show that antibiotic-induced microbiota perturbations compromise inflammatory monocytes and thereby impair antibacterial defence.

Su, Zhao, Jiang and colleagues identify IGFBP6 as an intrinsic downregulator of the inflammatory response lost in disturbed flow-induced atherosclerotic plaque development, suggesting that its restoration may represent a viable therapeutic strategy.

A growing number of G protein-coupled receptors (GPCRs) are being identified as sensors for ligands that are energy substrates or metabolic intermediates, and their central role in the coordination of metabolic processes is increasingly being recognized. Offermanns and colleagues summarize the function of these metabolite-sensing GPCRs in physiology and disease, and discuss the emerging pharmacological agents that are being developed to target these GPCRs for the treatment of metabolic disorders.

Semaphorins — a group of cell-surface and secreted proteins whose effects are mediated by plexin receptors — are involved in intercellular communication in the nervous system, the immune system and during angiogenesis. Worzfeld and Offermanns summarize the pathological roles of semaphorins and plexins in cancer, bone diseases, immuno-inflammatory diseases and spinal cord injury, and discuss emerging strategies to therapeutically target these molecules.

The authors report that endothelial protocadherin FAT1 inhibits endothelial proliferation and angiogenesis by promoting degradation of the transcriptional cofactors YAP and TAZ by direct interaction with the E3 ubiquitin ligase Mind Bomb-2 (MIB2).

Adipose tissue expansion occurs via enlargement of adipocytes as well as the generation of new fat cells, the latter being associated with more favorable metabolic outcomes. Here, the authors show that activation of adipocyte Piezo1 results in release of FGF1 and stimulates the differentiation of adipocyte precursor cells.

Despite significant advances in therapies, mortality and morbidity resulting from heart failure remain high. Here, the authors show that fibroblast-specific deletion of Protein kinase N (PKN) reduces myocardial fibrotic changes, indicating PKN as a potential therapeutic target for heart failure.

FFAR1 receptor is highly expressed in beta cells and its activation has been suggested as therapy against type-2 diabetes. Here, Tunaru et al. show that 20-hydroxyeicosatetraenoic acid, produced within the islets upon glucose stimulation, acts in an autocrine manner to stimulate insulin secretion via FFAR1 activation.

Smooth muscle cell-specific knockout of Tet3 in mice leads to loss of intragenic 5-hydroxymethylcytosine, accumulation of spurious transcripts and TLR7/8-mediated lung inflammation resembling asthma in human lung samples.

P2Y10 is a G-protein-coupled receptor that is expressed in CD4 T cells. Here authors show that its ligands, lysophosphatidylserine and ATP, are induced in T cells upon chemokine stimulation and regulate RhoA activation and migration through an autocrine/paracrine loop.

Tubulogenesis is required for the formation of many internal structures including the trachea. Here, the authors show that the potassium channel KCNJ13 regulates tracheal tube formation, with shorter tracheas forming in mutant mice due in part to changes in actin organization in tracheal smooth muscle cells.

While biallelic mutations of the SLC26A4 gene cause non-syndromic hearing loss with enlarged vestibular aqueducts or Pendred syndrome, a considerable number of patients carry mono-allelic mutations. Here the authors identify EPHA2 as another causative gene of Pendred syndrome with SLC26A4.

The role of macrophages in hypertension-induced arterial remodeling is poorly understood. Here, Sumida et al. show that high blood pressure drives the alternatively activated macrophages to secrete complement C1q protein, which in turn elicits proliferative β-catenin signalling in the arterial smooth muscle cells.

The ketone body β-hydroxybutyrate is produced in the liver in response to a ketogenic diet. Here, Rahman et al. show that β-hydroxybutyrate mediates the neuroprotective effect of a ketogenic diet by activating the HCA₂receptor on a neuroprotective subset of macrophages.

It is unclear how epithelial tissues adjust cell division rates to cell density. Here, the authors show that Plexin-B1 and Plexin-B2 sense mechanical compression (crowding) of epidermal stem cells, resulting in inactivation of YAP and suppression of cell proliferation.

Fat uptake and storage in subcutaneous adipose tissue (SAT) prevents ectopic fat accumulation and associated metabolic complications, however, the underlying mechanisms are incompletely understood. Here, the authors show that adipose angiopoietin-2 (Angpt2) enhances SAT size via increased endothelial fatty acid transport.

GPCRs are versatile cellular sensors for chemical stimuli but the molecular mechanisms underlying mechanically induced GPCR activation have remained elusive. Here authors identify the C-terminal helix 8 (H8) as the essential structural motif endowing H₁R and other GPCRs with mechanosensitivity.

The signalling cascade involved in lung ischaemia–reperfusion-induced oedema is poorly understood. Using knockout mice, Weissmannet al. propose a model in which reactive oxygen species production by endothelial NOX2 leads to phospholipase C-γ activation, DAG kinase inhibition and subsequent TRPC6 activation.

Dietary fibre is metabolized into short-chain fatty acids by gut bacteria. Here the authors show that these metabolites activate the NLRP3 inflammasome in gut epithelial cells and protect mice from injury-induced colitis, suggesting a mechanism for the benefits of a high-fibre diet.

TNF is typically viewed as an inflammatory mediator. Here the authors identify a non-inflammatory mechanism conserved across species whereby the constitutively expressed smooth muscle cell TNF mediates myogenic signal transduction in skeletal muscle resistance arteries and regulates mean arterial blood pressure.

The lipid sphingosine-1-phosphate (S1P) is known to mediate leukocyte recruitment in inflammation. Here, Nussbaum et al.show that S1P, via its receptor S1P3, also regulates leukocyte rolling on endothelium by promoting the presentation of the adhesion molecule P-selectin on the endothelial surface.

Physical exercise promotes brain angiogenesis through an unknown signalling cascade. Morlandet al. identify the elusive muscle-brain communication and show that lactate produced by muscle activity binds to its receptor HCAR1 in brain vessel-surrounding cells, stimulating VEGF production and brain angiogenesis.

Endothelial cells align in the direction of flow in response to shear stress. Here the authors describe a zebrafish model for visualization of endothelial polarization and demonstrate that endothelial cell alignment depends on blood flow and Apelin signalling.

Histamine causes vascular leakage by a direct and yet mechanistically poorly defined effect on endothelium. Here, the authors show that histamine elicits endothelial RhoA/Rock signaling and that inhibition of this pathway preserves the vascular barrier, thereby identifying novel pharmacological targets for histamine-mediated diseases.

Wu and colleagues delineate an mTORC2-dependent cell migration pathway. They show that stimulation of the Gα₁₂ protein subunit induces the ARAF/ERK-mediated expression of the RFFL E3 ubiquitin ligase. RFFL, in turn, targets the inhibitory PRR5L subunit of the mTORC2 complex for ubiquitylation and degradation, enabling mTORC2 to phosphorylate PKC-δ and promote cell migration.

The resting zone of the growth plate of mammalian long bones contains stem-like chondrocytes. Here, the authors show that G-protein stimulatory alpha subunit, Gsα, and the Gq/11α G-proteins together protect stem-like chondrocytes from apoptosis and preserve chondrocyte quiescence in mouse growth plates.

Inflammatory cytokines such as TNF-α influence inflammation, apoptosis and tumour development through regulation of the kinase IKKβ. Krishnan and Nolte et al.apply quantitative proteomics to identify potential IKKβ targets, and reveal phosphorylation of AEG-1 by IKKβ as a mechanism controlling NF-κB signalling.

Human and murine tumour cells induce programmed necrosis (necroptosis) of endothelial cells, which promotes tumour cell extravasation and metastasis.

Genetic deletion of two fatty acid receptors in beta cells improves insulin secretion and diabetes.

Constitutive deletion of Rcan1 has been previously shown to prevent Angiotensin II-induced aneurysm in mice. Here the authors show that tissue-specific inducible deletion of Rcan1 in vascular cell types predisposes to hypertension-mediated aortic rupture, intramural hematoma, and aneurysm, due to increased GSK-3b-mediated activation of ROCK and induction of a hypercontractile phenotype.

Wnt signaling is known to regulate the formation of the blood-brain barrier. Here Hübner et al. dissect the underlying mechanisms using high resolution live imaging in zebrafish, and find that Wnt regulates anastomosis of angiogenic sprouts in the brain by counteracting sphingosine-1-phosphate receptor signaling.

The hypothalamic-pituitary-thyroid (HPT) axis regulates a wide range of physiological processes. Here the authors show that hypothalamic tanycytes play a role in the homeostatic regulation of the HPT axis; activation of TRH signaling in tanycytes elevates their intracellular Ca²⁺ via Gα_q/11 pathway, ultimately resulting in reduced TRH release into the pituitary vessels.