Activation of DP1 by PGD2 in macrophages induces the binding of PRKAR2A to the IFN-γR2 transmembrane region, inhibits JAK2/STAT1 signaling, and triggers the expression of antiinflammatory and reparative genes in myocardial infarction and sepsis.

Niacin, as an antidyslipidemic drug, elicits a strong flushing response by release of prostaglandin (PG) D2. However, whether niacin is beneficial for inflammatory bowel disease (IBD) remains unclear. Here, we observed niacin administration‐enhanced PGD2 production in colon tissues in dextran sulfate sodium (DSS)‐challenged mice, and protected mice against DSS or 2,4,6‐trinitrobenzene sulfonic acid (TNBS)‐induced colitis in D prostanoid receptor 1 (DP1)‐dependent manner. Specific ablation of DP1 receptor in vascular endothelial cells, colonic epithelium, and myeloid cells augmented DSS/TNBS‐induced colitis in mice through increasing vascular permeability, promoting apoptosis of epithelial cells, and stimulating pro‐inflammatory cytokine secretion of macrophages, respectively. Niacin treatment improved vascular permeability, reduced apoptotic epithelial cells, promoted epithelial cell update, and suppressed pro‐inflammatory gene expression of macrophages. Moreover, treatment with niacin‐containing retention enema effectively promoted UC clinical remission and mucosal healing in patients with moderately active disease. Therefore, niacin displayed multiple beneficial effects on DSS/TNBS‐induced colitis in mice by activation of PGD2/DP1 axis. The potential efficacy of niacin in management of IBD warrants further investigation.

Gluconeogenesis is drastically increased in patients with type 2 diabetes and accounts for increased fasting plasma glucose concentrations. Circulating levels of prostaglandin (PG) F are also markedly elevated in diabetes; however, whether and how PGF regulates hepatic glucose metabolism remain unknown. Here, we demonstrated that PGF receptor (F-prostanoid receptor [FP]) was upregulated in the livers of mice upon fasting- and diabetic stress. Hepatic deletion of the FP receptor suppressed fasting-induced hepatic gluconeogenesis, whereas FP overexpression enhanced hepatic gluconeogenesis in mice. FP activation promoted the expression of gluconeogenic enzymes (PEPCK and glucose-6-phosphatase) in hepatocytes in a FOXO1-dependent manner. Additionally, FP coupled with G in hepatocytes to elicit Ca release, which activated Ca/calmodulin-activated protein kinase IIγ (CaMKIIγ) to increase FOXO1 phosphorylation and subsequently accelerate its nuclear translocation. Blockage of p38 disrupted CaMKIIγ-induced FOXO1 nuclear translocation and abrogated FP-mediated hepatic gluconeogenesis in mice. Moreover, knockdown of hepatic FP receptor improved insulin sensitivity and glucose homeostasis in / mice. FP-mediated hepatic gluconeogenesis via the CaMKIIγ/p38/FOXO1 signaling pathway, indicating that the FP receptor might be a promising therapeutic target for type 2 diabetes.

Pulmonary arterial hypertension (PAH) is a life-threatening disease characterized by progressive pulmonary artery (PA) remodeling. T helper 2 cell (Th2) immune response is involved in PA remodeling during PAH progression. Here, we found that CRTH2 (chemoattractant receptor homologous molecule expressed on Th2 cell) expression was up-regulated in circulating CD3CD4 T cells in patients with idiopathic PAH and in rodent PAH models. CRTH2 disruption dramatically ameliorated PA remodeling and pulmonary hypertension in different PAH mouse models. CRTH2 deficiency suppressed Th2 activation, including IL-4 and IL-13 secretion. Both CRTH2 bone marrow reconstitution and CRTH2 CD4 T cell adoptive transfer deteriorated hypoxia + ovalbumininduced PAH in CRTH2 mice, which was reversed by dual neutralization of IL-4 and IL-13. CRTH2 inhibition alleviated established PAH in mice by repressing Th2 activity. In culture, CRTH2 activation in Th2 cells promoted pulmonary arterial smooth muscle cell proliferation through activation of STAT6. These results demonstrate the critical role of CRTH2-mediated Th2 response in PAH pathogenesis and highlight the CRTH2 receptor as a potential therapeutic target for PAH.

Apoptotic death of cardiac myocytes is associated with ischemic heart disease and chemotherapy‐induced cardiomyopathy. Chemoattractant receptor‐homologous molecule expressed on T helper type 2 cells (CRTH2) is highly expressed in the heart. However, its specific role in ischemic cardiomyopathy is not fully understood. Here, we demonstrated that CRTH2 disruption markedly improved cardiac recovery in mice postmyocardial infarction and doxorubicin challenge by suppressing cardiomyocyte apoptosis. Mechanistically, CRTH2 activation specifically facilitated endoplasmic reticulum (ER) stress‐induced cardiomyocyte apoptosis via caspase‐12‐dependent pathway. Blockage of m‐calpain prevented CRTH2‐mediated cardiomyocyte apoptosis under ER stress by suppressing caspase‐12 activity. CRTH2 was coupled with Gαq to elicit intracellular Ca2+ flux and activated m‐calpain/caspase‐12 cascade in cardiomyocytes. Knockdown of caspase‐4, an alternative to caspase‐12 in humans, markedly alleviated CRHT2 activation‐induced apoptosis in human cardiomyocyte response to anoxia. Our findings revealed an unexpected role of CRTH2 in promoting ER stress‐induced cardiomyocyte apoptosis, suggesting that CRTH2 inhibition has therapeutic potential for ischemic cardiomyopathy.

This article is part of a themed section on Spotlight on Small Molecules in Cardiovascular Diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.8/issuetoc.

Two distinct monocyte (Mo)/macrophage (Mp) subsets (Ly6Clow and Ly6Chigh) orchestrate cardiac recovery process following myocardial infarction (MI). Prostaglandin (PG) E2 is involved in the Mo/Mp-mediated inflammatory response, however, the role of its receptors in Mos/Mps in cardiac healing remains to be determined. Here we show that pharmacological inhibition or gene ablation of the Ep3 receptor in mice suppresses accumulation of Ly6Clow Mos/Mps in infarcted hearts. Ep3 deletion in Mos/Mps markedly attenuates healing after MI by reducing neovascularization in peri-infarct zones. Ep3 deficiency diminishes CX3C chemokine receptor 1 (CX3CR1) expression and vascular endothelial growth factor (VEGF) secretion in Mos/Mps by suppressing TGFβ1 signalling and subsequently inhibits Ly6Clow Mos/Mps migration and angiogenesis. Targeted overexpression of Ep3 receptors in Mos/Mps improves wound healing by enhancing angiogenesis. Thus, the PGE2/Ep3 axis promotes cardiac healing after MI by activating reparative Ly6Clow Mos/Mps, indicating that Ep3 receptor activation may be a promising therapeutic target for acute MI.

c L-Arginine and L-arginine-metabolizing enzymes play important roles in the biology of some types of myeloid cells, including macrophage and myeloid-derived suppressor cells. In this study, we found evidence that arginase 1 (Arg1) is required for the differentiation of mouse dendritic cells (DCs). Expression of Arg1 was robustly induced during monocyte-derived DC differentiation. Ectopic expression of Arg1 significantly promoted monocytic DC differentiation in a granulocyte-macrophage colonystimulating factor culture system and also facilitated the differentiation of CD8␣ ؉ conventional DCs in the presence of Flt3 ligand. Knockdown of Arg1 reversed these effects. Mechanistic studies showed that the induced expression of Arg1 in differentiating DCs was caused by enhanced recruitment of histone deacetylase 4 (HDAC4) to the Arg1 promoter region, which led to a reduction in the acetylation of both the histone 3 and STAT6 proteins and subsequent transcriptional activation of Arg1. Further investigation identified a novel STAT6 binding site within the Arg1 promoter that mediated its regulation by STAT6 and HDAC4. These observations suggest that the cross talk between HDAC4 and STAT6 is an important regulatory mechanism of Arg1 transcription in DCs. Moreover, overexpression of Arg1 clearly abrogated the ability of HDAC inhibitors to suppress DC differentiation. In conclusion, we show that Arg1 is a novel regulator of myeloid DC differentiation. Dendritic cells (DCs) are specialized antigen-presenting cells that capture, process, and present antigens to T cells and thereby play important roles in both innate and adaptive immunity (1, 2). Differentiation of DCs from hematopoietic progenitor cells (HPCs) is regulated by complex signaling pathways that involve soluble cytokines and transcription factors (TFs) in bone marrow (BM) and peripheral lymphoid tissues (3, 4). Impaired DC differentiation facilitates the escape of tumor cells and invading pathogens from the host's immune surveillance (5-7). Although many molecular mechanisms linked to DC differentiation have been proposed, a complete picture has yet to be obtained (8-10).L-Arginine is a conditionally essential amino acid in adult mammals because it is required under some special circumstances such as trauma, pregnancy, and infections. L-Arginine is metabolized by arginase (Arg) to produce urea and L-ornithine and by nitric oxide synthase to produce nitric oxide and L-citrulline. There are two known Arg isoforms, Arg1 and Arg2. Arg1 is constitutively expressed in the liver, where it participates in the urea cycle, while Arg2 is located in mitochondria in various cell types (11). Recently, it was reported that Arg1 expression is induced in myeloid cells exposed to Th2 cytokines such as interleukin-4 (IL-4) and IL-13. Induction of Arg1 or Nos2 has been used to distinguish macrophages activated through either the classical or the alternative pathway (12). Upregulation of Arg1 and Nos2 is closely associated with the suppressive activity of myeloid-derived suppressor cel...