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Nonalcoholic steatohepatitis (NASH) is characterized by progressive liver injury, inflammation, and fibrosis; however, the mechanisms that govern the transition from hepatic steatosis, which is relatively benign, to NASH remain poorly defined. Neuregulin 4 (Nrg4) is an adipose tissue-enriched endocrine factor that elicits beneficial metabolic effects in obesity. Here, we show that Nrg4 is a key component of an endocrine checkpoint that preserves hepatocyte health and counters diet-induced NASH in mice. Nrg4 deficiency accelerated liver injury, fibrosis, inflammation, and cell death in a mouse model of NASH. In contrast, transgenic expression of Nrg4 in adipose tissue alleviated diet-induced NASH. Nrg4 attenuated hepatocyte death in a cell-autonomous manner by blocking ubiquitination and proteasomal degradation of c-FLIPL, a negative regulator of cell death. Adeno-associated virus-mediated (AAV-mediated) rescue of hepatic c-FLIPL expression in Nrg4-deficent mice functionally restored the brake for steatosis to NASH transition. Thus, hepatic Nrg4 signaling serves as an endocrine checkpoint for steatosis-to-NASH progression by activating a cytoprotective pathway to counter stress-induced liver injury.

Activation of brown adipose tissue-mediated thermogenesis is a strategy for tackling obesity and promoting metabolic health. BMP8b is secreted by brown/beige adipocytes and enhances energy dissipation. Here we show that adipocyte-secreted BMP8b contributes to adrenergic-induced remodeling of the neuro-vascular network in adipose tissue (AT). Overexpression of bmp8b in AT enhances browning of the subcutaneous depot and maximal thermogenic capacity. Moreover, BMP8b-induced browning, increased sympathetic innervation and vascularization of AT were maintained at 28 °C, a condition of low adrenergic output. This reinforces the local trophic effect of BMP8b. Innervation and vascular remodeling effects required BMP8b signaling through the adipocytes to 1) secrete neuregulin-4 (NRG4), which promotes sympathetic axon growth and branching in vitro, and 2) induce a pro-angiogenic transcriptional and secretory profile that promotes vascular sprouting. Thus, BMP8b and NRG4 can be considered as interconnected regulators of neuro-vascular remodeling in AT and are potential therapeutic targets in obesity. Enhancing thermogenesis is a promising therapeutic strategy for promoting metabolic health. Here the authors show that adipocyte-secreted BMP8b contributes to optimizing the thermogenic response by remodeling of the neuro-vascular networks in brown and white adipose tissue.

The adipokine Neuregulin 4 (Nrg4) protects against obesity-induced insulin resistance. Here, we analyze how the downregulation of Nrg4 influences insulin action and the underlying mechanisms in adipocytes. Validated shRNA lentiviral vectors were used to generate scramble (Scr) and Nrg4 knockdown (KD) 3T3-L1 adipocytes. Adipogenesis was unaffected in Nrg4 KD adipocytes, but there was a complete impairment of the insulin-induced 2-deoxyglucose uptake, which was likely the result of reduced insulin receptor and Glut4 protein. Downregulation of Nrg4 enhanced the expression of proinflammatory cytokines. Anti-inflammatory agents recovered the insulin receptor, but not Glut4, content. Proteins enriched in Glut4 storage vesicles such as the insulin-responsive aminopeptidase (IRAP) and Syntaxin-6 as well as TBC1D4, a protein involved in the intracellular retention of Glut4 vesicles, also decreased by Nrg4 KD. Insulin failed to reduce autophagy in Nrg4 KD adipocytes, observed by a minor effect on mTOR phosphorylation, at the time that proteins involved in autophagy such as LC3-II, Rab11, and Clathrin were markedly upregulated. The lysosomal activity inhibitor bafilomycin A1 restored Glut4, IRAP, Syntaxin-6, and TBC1D4 content to those found in control adipocytes. Our study reveals that Nrg4 preserves the insulin responsiveness by preventing inflammation and, in turn, benefits the insulin regulation of autophagy.

Osteoarthritis (OA) is a chronic inflammatory disease characterized by synovial inflammation and cartilage degradation. Synovial macrophages, as a key driver of OA progression, during all stages of OA and induced to produce inflammatory cytokines that aggravate the degradation of cartilage. Here, we demonstrate that neuregulin-4 (Nrg4) deficiency exacerbates synovial pro-inflammatory macrophage transformation and articular cartilage abrasion in a mouse model of OA. Conversely, Nrg4 re-expression significantly reduces pro-inflammatory macrophage accumulation and synovial inflammation, thereby attenuating OA progression. Mechanistically, Nrg4 activates the ErbB4/Stat5b signaling pathway, which subsequently suppresses NF-κB activation, leading to reduced pro-inflammatory macrophage transformation and pro-inflammatory cytokine production. In vitro experiments further confirm that Nrg4 directly inhibits macrophage infiltration. These findings reveal a novel role for Nrg4 in modulating synovial macrophage transformation through the ErbB4/Stat5b/NF-κB axis, offering a potential therapeutic strategy for OA by targeting synovial inflammation. This study also expands our understanding of OA protection beyond chondrocyte protection, emphasizing its role in regulating the synovial microenvironment and cartilage homeostasis in OA.

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal disease affecting the neuromuscular system. While there have been a number of important genetic discoveries, there are no therapeutics capable of stopping its insidious progression. Lessons from clinical histories reveal that ALS can start focally at a single limb, but then segmentally spread up and down the spinal cord as well as in the motor cortex and cortex of frontal and temporal lobes until respiratory muscles fail. With or without a clear genetic etiology, often there is no explanation as to why it starts in one region of the body versus another. Similarly, once the disease starts the mechanisms by which the neurodegenerative process spreads are not known. Here, we summarize recent work in animal models that support the hypothesis that critical environmental contributions, such as a nerve injury, can initiate the disease process. We also propose that pathological axoglial signaling by the glial growth factor neuregulin-1 leads to the slow propagation of neuroinflammation resulting in neurodegeneration up and down the spinal cord and that locally applied drugs that block neuregulin-1 signaling could slow or halt the spread of disease.

Most of the enteric nervous system derives from the “vagal” neural crest, lying at the level of somites 1–7, which invades the digestive tract rostro-caudally from the foregut to the hindgut. Little is known about the initial phase of this colonization, which brings enteric precursors into the foregut. Here we show that the “vagal crest” subsumes two populations of enteric precursors with contrasted origins, initial modes of migration, and destinations. Crest cells adjacent to somites 1 and 2 produce Schwann cell precursors that colonize the vagus nerve, which in turn guides them into the esophagus and stomach. Crest cells adjacent to somites 3–7 belong to the crest streams contributing to sympathetic chains: they migrate ventrally, seed the sympathetic chains, and colonize the entire digestive tract thence. Accordingly, enteric ganglia, like sympathetic ones, are atrophic when deprived of signaling through the tyrosine kinase receptor ErbB3, while half of the esophageal ganglia require, like parasympathetic ones, the nerve-associated form of the ErbB3 ligand, Neuregulin-1. These dependencies might bear relevance to Hirschsprung disease, with which alleles of Neuregulin-1 are associated.

In vertebrate hearts, the ventricular trabecular myocardium develops as a sponge-like network of cardiomyocytes that is critical for contraction and conduction, ventricular septation, papillary muscle formation and wall thickening through the process of compaction 1 . Defective trabeculation leads to embryonic lethality 2 – 4 or non-compaction cardiomyopathy (NCC) 5 . There are divergent views on when and how trabeculation is initiated in different species. In zebrafish, trabecular cardiomyocytes extrude from compact myocardium 6 , whereas in chicks, chamber wall thickening occurs before overt trabeculation 7 . In mice, the onset of trabeculation has not been described, but is proposed to begin at embryonic day 9.0, when cardiomyocytes form radially oriented ribs 2 . Endocardium–myocardium communication is essential for trabeculation, and numerous signalling pathways have been identified, including Notch 2 , 8 and Neuregulin (NRG) 4 . Late disruption of the Notch pathway causes NCC 5 . Whereas it has been shown that mutations in the extracellular matrix (ECM) genes Has2 and Vcan prevent the formation of trabeculae in mice 9 , 10 and the matrix metalloprotease ADAMTS1 promotes trabecular termination 3 , the pathways involved in ECM dynamics and the molecular regulation of trabeculation during its early phases remain unexplored. Here we present a model of trabeculation in mice that integrates dynamic endocardial and myocardial cell behaviours and ECM remodelling, and reveal new epistatic relationships between the involved signalling pathways. NOTCH1 signalling promotes ECM degradation during the formation of endocardial projections that are critical for individualization of trabecular units, whereas NRG1 promotes myocardial ECM synthesis, which is necessary for trabecular rearrangement and growth. These systems interconnect through NRG1 control of Vegfa , but act antagonistically to establish trabecular architecture. These insights enabled the prediction of persistent ECM and cardiomyocyte growth in a mouse NCC model, providing new insights into the pathophysiology of congenital heart disease. A new model of cardiac trabeculation in mice is presented in which NOTCH1 and NRG1 have opposing roles in extracellular matrix degradation and synthesis that are essential for defining trabecular architecture.

Neuregulin 2 (NRG2) belongs to the EGF family of growth factors. Most of this family members require proteolytic cleavage to liberate their ectodomains capable of binding and activating their cognate ErbB receptors. To date, most of the studies investigating proteolytic processing of neuregulins focused on NRG1, which was shown to undergo ectodomain shedding by several ADAM proteases and BACE1 and the remaining fragment was further cleaved by γ-secretase. Recently, NRG2 attracted more attention due to its role in the neurogenesis and modulation of behaviors associated with psychiatric disorders. In this study, we used genetic engineering methods to identify proteases involved in proteolytic processing of murine NRG2. Using non-neuronal cell lines as well as cultures of primary hippocampal neurons, we demonstrated that the major proteases responsible for releasing NRG2 ectodomain are ADAM10 and BACE2. Co-expression of NRG2 and BACE2 in neurons of certain brain structures including medulla oblongata and cerebellar deep nuclei was confirmed via immunohistochemical staining. The cleavage of NRG2 by ADAM10 or BACE2 generates a C-terminal fragment that serves as a substrate for γ-secretase. We also showed that murine NRG2 is subject to post-translational modifications, substantial glycosylation of its extracellular part, and phosphorylation of the cytoplasmic tail.

Neuregulin‐1 (NRG‐1) is reported to be cardioprotective through the extracellular‐regulated protein kinase (ERK) 1/2 pathway in myocardial ischaemia‐reperfusion injury (MIRI). NOX4‐induced ROS activated NLRP3 inflammasome and exacerbates MIRI. This study aims to investigate whether NRG‐1 can suppress NOX4 by ERK1/2 and consequently inhibit the NLRP3/caspase‐1 signal in MIRI. The myocardial infarct size (IS) was measured by TTC‐Evans blue staining. Immunohistochemical staining, real‐time quantitative PCR (RT‐qPCR) and Western blotting were used for detection of the factors, such as NOX4, ERK1/2, NLRP3, caspase‐1 and IL‐1β .The IS in the NRG‐1 (3 μg/kg, intravenous) group was lower than that in the IR group. Immunohistochemical analysis revealed NRG‐1 decreased 4HNE and NOX4. The RT‐qPCR and Western blot analyses revealed that NRG‐1 mitigated the IR‐induced up‐regulation of NOX4 and ROS production. Compared with the IR group, the NRG‐1 group exhibited a higher level of P‐ERK1/2 and a lower level of NLRP3. In the Langendorff model, PD98059 inhibited ERK1/2 and up‐regulated the expression of NOX4, NLRP3, caspase‐1 and IL‐1β, which exacerbated oxidative stress and inflammation. In conclusion, NRG‐1 can reduce ROS production by inhibiting NOX4 through ERK1/2 and inhibit the NLRP3/caspase‐1 pathway to attenuate myocardial oxidative damage and inflammation in MIRI.

BackgroundFive-weekly S-1 plus cisplatin (SP) therapy is the standard care for advanced gastric or esophagogastric junction cancer (GC/EGJC) in East Asia. However, its efficacy and safety when combined with trastuzumab therapy for human epidermal growth factor receptor 2 (HER2)-positive advanced GC/EGJC remains unclear.MethodsPatients received 5-weekly SP therapy (S-1 at 40–60 mg twice daily for 21 days plus cisplatin at 60 mg/m2 on day 8, every 5 weeks) plus trastuzumab therapy (first dose of 8 mg/kg, then 6 mg/kg every 3 weeks). The primary end point was the response rate, and the secondary end points included progression-free survival, overall survival, safety, and serum biomarker levels.ResultsForty-four patients were enrolled. The response rate, progression-free survival, and overall survival were 61% (95% confidence interval 46–76%), 5.9 months, and 16.5 months respectively. The commonest grade 3 or grade 4 adverse events were neutropenia (30%) and anorexia (25%). A significantly higher response rate (92% vs 43%; P = 0.008) and longer progression-free survival (median 14.5 months vs 4.2 months; P = 0.028) were observed in patients with high (n = 14) compared with low (n = 17) pretreatment serum neuregulin 1 levels.ConclusionsFive-weekly SP therapy combined with trastuzumab therapy showed a good antitumor response and acceptable toxicity in HER2-positive advanced GC/EGJC. Serum neuregulin 1 might be associated with the efficacy of this treatment regimen.