Interorgan Signaling Research Articles

Integrative Physiology of Pneumonia.

Pneumonia is a type of acute lower respiratory infection that is common and severe. The outcome of lower respiratory infection is determined by the degrees to which immunity is protective and inflammation is damaging. Intercellular and interorgan signaling networks coordinate these actions to fight infection and protect the tissue. Cells residing in the lung initiate and steer these responses, with additional immunity effectors recruited from the bloodstream. Responses of extrapulmonary tissues, including the liver, bone marrow, and others, are essential to resistance and resilience. Responses in the lung and extrapulmonary organs can also be counterproductive and drive acute and chronic comorbidities after respiratory infection. This review discusses cell-specific and organ-specific roles in the integrated physiological response to acute lung infection, and the mechanisms by which intercellular and interorgan signaling contribute to host defense and healthy respiratory physiology or to acute lung injury, chronic pulmonary disease, and adverse extrapulmonary sequelae. Pneumonia should no longer be perceived as simply an acute infection of the lung. Pneumonia susceptibility reflects ongoing and poorly understood chronic conditions, and pneumonia results in diverse and often persistent deleterious consequences for multiple physiological systems.

The release of cardioprotective humoral factors after remote ischemic preconditioning in humans is age- and sex-dependent

BackgroundPreclinical and proof-of-concept studies suggest a cardioprotective effect of remote ischemic preconditioning (RIPC). However, two major clinical trials (ERICCA and RIPHeart) failed to show cardioprotection by RIPC. Aging and gender might be confounding factors of RIPC affecting the inter-organ signalling. Theoretically, confounding factors might prevent the protective potency of RIPC by interfering with cardiac signalling pathways, i.e. at the heart, and/or by affecting the release of humoral factor(s) from the remote organ, e.g. from the upper limb. This study investigated the effect of age and sex on the release of cardioprotective humoral factor(s) after RIPC in humans.MethodsBlood samples were taken from young and aged, male and female volunteers before (control) and after RIPC (RIPC). To investigate the protective potency of the different plasma groups obtained from the human volunteers, isolated perfused hearts of young rats were used as bioassay. For this, hearts were perfused with the volunteer plasma (0.5% of coronary flow) before hearts underwent global ischemia and reperfusion. In addition, to characterize the protective potency of humoral factor(s) after RIPC to initiate protection not only in young but also aged hearts, plasma from young male volunteers were transferred to isolated hearts of aged rats. At the end of the experimental protocol, infarct sizes were determined by TTC-staining (expressed as % of left ventricle).ResultsRIPC plasma of young male volunteers reduced infarct size in young rat hearts from 47 ± 5 to 31 ± 10% (p = 0.02). In contrast, RIPC plasma of aged male volunteers had no protective effect. Infarct size after application of control plasma of young female volunteers was 33 ± 10%, and female RIPC plasma did not lead to an infarct size reduction. RIPC plasma of old female initiated no cardioprotection. RIPC plasma of young male volunteers reduced infarct size in isolated hearts from aged rats (41 ± 5% vs. 51 ± 5%; p < 0.001).ConclusionsThe release of humoral factor(s) into the blood after RIPC in humans is affected by both age and sex. In addition, these blood borne factor(s) are capable to initiate cardioprotection within the aged heart.

Caenorhabditis elegans DBL-1/BMP Regulates Lipid Accumulation via Interaction with Insulin Signaling.

Metabolic homeostasis is coordinately controlled by diverse inputs. Understanding these regulatory networks is vital to combating metabolic disorders. The nematode Caenorhabditis elegans has emerged as a powerful, genetically tractable model system for the discovery of lipid regulatory mechanisms. Here we introduce DBL-1, the C. elegans homolog of bone morphogenetic protein 2/4 (BMP2/4), as a significant regulator of lipid homeostasis. We used neutral lipid staining and a lipid droplet marker to demonstrate that both increases and decreases in DBL-1/BMP signaling result in reduced lipid stores and lipid droplet count. We find that lipid droplet size, however, correlates positively with the level of DBL-1/BMP signaling. Regulation of lipid accumulation in the intestine occurs through non-cell-autonomous signaling, since expression of SMA-3, a Smad signal transducer, in the epidermis (hypodermis) is sufficient to rescue the loss of lipid accumulation. Finally, genetic evidence indicates that DBL-1/BMP functions upstream of Insulin/IGF-1 Signaling in lipid metabolism. We conclude that BMP signaling regulates lipid metabolism in C. elegans through interorgan signaling to the Insulin pathway, shedding light on a less well-studied regulatory mechanism for metabolic homeostasis.

Bi-stability in type 2 diabetes mellitus multi-organ signalling network.

Type 2 diabetes mellitus (T2DM) is believed to be irreversible although no component of the pathophysiology is irreversible. We show here with a network model that the apparent irreversibility is contributed by the structure of the network of inter-organ signalling. A network model comprising all known inter-organ signals in T2DM showed bi-stability with one insulin sensitive and one insulin resistant attractor. The bi-stability was made robust by multiple positive feedback loops suggesting an evolved allostatic system rather than a homeostatic system. In the absence of the complete network, impaired insulin signalling alone failed to give a stable insulin resistant or hyperglycemic state. The model made a number of correlational predictions many of which were validated by empirical data. The current treatment practice targeting obesity, insulin resistance, beta cell function and normalization of plasma glucose failed to reverse T2DM in the model. However certain behavioural and neuro-endocrine interventions ensured a reversal. These results suggest novel prevention and treatment approaches which need to be tested empirically.

Inter-organ regulation of haem homeostasis.

Haem is an iron-containing cofactor required for life. Many cellular processes rely on haem and failure to maintain iron homeostasis results in numerous pathological conditions. A study now identifies a Caenorhabditis elegans inter-organ signalling pathway in which secreted intestinal HRG-7 and neuronally secreted BMP signals coordinate animal haem homeostasis.

Inter-organ signalling by HRG-7 promotes systemic haem homeostasis.

Growing evidence in vertebrates predicts that cellular haem levels in animals are maintained not only by a cell's internal capacityfor haem synthesis in a cell-autonomous manner, but also by an inter-organ haem trafficking network through cell-non-autonomous regulation. Using Caenorhabditiselegans, a genetically and optically amenable animal model for visualizing haem-dependent signalling, we show that HRG-7, a protein with homology to aspartic proteases, mediates inter-organ signalling between the intestine and extra-intestinal tissues. Intestinal HRG-7 functions as a secreted signalling factor during haem starvation in extra-intestinal tissues and is regulated through a DBL-1, homologous to BMP5, dependent signal from neurons. Given the evidence that vertebrate homologues exist for each of the components of the HRG-7-mediated signalling pathway, it is conceivable that the cell-non-autonomous signalling framework that we uncovered in C.elegans may have functional relevance for inter-organ regulation of iron and haem metabolism in humans.

Bile Acid Control of Metabolism and Inflammation in Obesity, Type 2 Diabetes, Dyslipidemia, and Nonalcoholic Fatty Liver Disease

Bile acids are signaling molecules that coordinately regulate metabolism and inflammation via the nuclear farnesoid X receptor (FXR) and the Takeda G protein-coupled receptor 5 (TGR5). These receptors activate transcriptional networks and signaling cascades controlling the expression and activity of genes involved in bile acid, lipid and carbohydrate metabolism, energy expenditure, and inflammation by acting predominantly in enterohepatic tissues, but also in peripheral organs. In this review, we discuss the most recent findings on the inter-organ signaling and interplay with the gut microbiota of bile acids and their receptors in meta-inflammation, with a focus on their pathophysiologic roles in obesity, type 2 diabetes, dyslipidemia, and nonalcoholic steatohepatitis, and their potential therapeutic applications.

Interorgan regulation of Drosophila intestinal stem cell proliferation by a hybrid organ boundary zone.

The molecular identities and regulation of cells at interorgan boundaries are often unclear, despite the increasingly appreciated role of organ boundaries in disease. Using Drosophila as a model, we here show that a specific population of adult midgut organ-boundary intestinal stem cells (OB-ISCs) is regulated by the neighboring hindgut, a developmentally distinct organ. This distinct OB-ISC control occurs through proximity to a specialized transition zone between the endodermal midgut and ectodermal hindgut that shares molecular signatures of both organs, which we term the hybrid zone (HZ). During homeostasis, proximity to the HZ restrains OB-ISC proliferation. However, injury to the adult HZ/hindgut drives upregulation of unpaired-3 cytokine, which signals through a Signal transducer and activator of transcription (STAT) protein to promote cell division only in OB-ISCs. If HZ disruption is severe, hyperplastic OB-ISCs expand across the interorgan boundary. Our data suggest that interorgan signaling plays an important role in controlling OB-ISCs in homeostasis and injury repair, which is likely to be crucial in prevention of disease.

Defining the interorgan communication network: systemic coordination of organismal cellular processes under homeostasis and localized stress

Following the acquisition of multicellularity, organisms with increasing levels of specialized cells, tissues, and organs emerged during evolution. To coordinate specialized organs, long-distance interorgan communication systems appeared. The central nervous system evolved to regulate many organ behaviors, using hormones or neurons. In addition, organs developed systems to directly communicate their states to one another. This is illustrated by the lack of nervous systems in plants and simple animals like sponges, which can perform complex systemic functions (Lough and Lucas, 2006; Srivastava et al., 2010). Developmental or homeostatic events within cells or tissues have been extensively studied. For example, maintenance of the integrity of the Drosophila gut involves stem cell proliferation and differentiation, partially driven by local JAK/STAT, EGF, MAPK, and Wnt signaling (Panayidou and Apidianakis, 2013). Recently, it has become clear that individual organs themselves are also able to communicate their states. However, the nature of the interorgan signaling mechanisms remains largely a mystery. Here, we review the emerging data supporting the existence of a vast interorgan communication network (ICN). The ICN is the network of peptides, proteins, and metabolites that act between organs to coordinate essential and specialized cellular processes under homeostasis and stress (Figure ​(Figure1).1). We propose that studies in Drosophila, where, unlike in mammals, biochemical studies can be combined with genome-wide in vivo tissue-specific genetic screens, are poised to identify many ICN components. Characterization of the ICN will further understanding of systemic diseases such as cancer-associated muscle cachexia. Figure 1 Overview of the interorgan communication network (ICN). The ICN is the network of peptides, proteins, and metabolites that act between organs to coordinate organismal cellular processes under homeostasis and stress. Organs in the body secrete factors ...

In Vivo Screening for Secreted Proteins That Modulate Glucose Handling Identifies Interleukin-6 Family Members as Potent Hypoglycemic Agents

Diabetes is a disease of abnormal glucose homeostasis characterized by chronic hyperglycemia and a broad array of consequent organ damage. Because normal glucose homeostasis is maintained by a complex interaction between behavior (feeding and physical activity) and metabolic activity that is modulated by inter-organ signaling through secreted factors, disease modeling in vitro is necessarily limited. In contrast, in vivo studies allow complex metabolic phenotypes to be studied but present a barrier to high throughput studies. Here we present the development of a novel in vivo screening platform that addresses this primary limitation of in vivo experimentation. Our platform leverages the large secretory capacity of the liver and the hepatocyte transfection technique of hydrodynamic tail vein injection to achieve supraphysiologic blood levels of secreted proteins. To date, the utility of hydrodynamic transfection has been limited by the deleterious impact of the variable transfection efficiency inherent to this technique. We overcome this constraint by co-transfection of a secreted luciferase cDNA whose product can be easily monitored in the blood of a living animal and used as a surrogate marker for transfection efficiency and gene expression levels. To demonstrate the utility of our strategy, we screened 248 secreted proteins for the ability to enhance glucose tolerance. Surprisingly, interleukin-6 and several of its family members but not other well-recognized insulin sensitizing agents were identified as potent hypoglycemic factors. We propose this experimental system as a powerful and flexible in vivo screening platform for identifying genes that modulate complex behavioral and metabolic phenotypes.

Photosynthetic sucrose acts as cotyledon-derived long-distance signal to control root growth during early seedling development in Arabidopsis

The most hazardous span in the life of green plants is the period after germination when the developing seedling must reach the state of autotrophy before the nutrients stored in the seed are exhausted. The need for an economically optimized utilization of limited resources in this critical period is particularly obvious in species adopting the dispersal strategy of producing a large amount of tiny seeds. The model plant Arabidopsis thaliana belongs to this category. Arabidopsis seedlings promote root development only in the light. This response to light has long been recognized and recently discussed in terms of an organ-autonomous feature of photomorphogenesis directed by the red/blue light absorbing photoreceptors phytochrome and cryptochrome and mediated by hormones such as auxin and/or gibberellin. Here we show that the primary root of young Arabidopsis seedlings responds to an interorgan signal from the cotyledons and that phloem transport of photosynthesis-derived sugar into the root tip is necessary and sufficient for the regulation of root elongation growth by light.

Exercise tames the wild side of the Myc network: a hypothesis

We propose that the well-documented therapeutic actions of repeated physical activities over human lifespan are mediated by the rapidly turning over proto-oncogenic Myc (myelocytomatosis) network of transcription factors. This transcription factor network is unique in utilizing promoter and epigenomic (acetylation/deacetylation, methylation/demethylation) mechanisms for controlling genes that include those encoding intermediary metabolism (the primary source of acetyl groups), mitochondrial functions and biogenesis, and coupling their expression with regulation of cell growth and proliferation. We further propose that remote functioning of the network occurs because there are two arms of this network, which consists of driver cells (e.g., working myocytes) that metabolize carbohydrates, fats, proteins, and oxygen and produce redox-modulating metabolites such as H₂O₂, NAD⁺, and lactate. The exercise-induced products represent autocrine, paracrine, or endocrine signals for target recipient cells (e.g., aortic endothelium, hepatocytes, and pancreatic β-cells) in which the metabolic signals are coupled with genomic networks and interorgan signaling is activated. And finally, we propose that lactate, the major metabolite released from working muscles and transported into recipient cells, links the two arms of the signaling pathway. Recently discovered contributions of the Myc network in stem cell development and maintenance further suggest that regular physical activity may prevent age-related diseases such as cardiovascular pathologies, cancers, diabetes, and neurological functions through prevention of stem cell dysfunctions and depletion with aging. Hence, regular physical activities may attenuate the various deleterious effects of the Myc network on health, the wild side of the Myc-network, through modulating transcription of genes associated with glucose and energy metabolism and maintain a healthy human status.

The true story of palmitoleic acid: Between myth and reality

The true story of palmitoleic acid: Between myth and reality

Functional genetic mouse models: promising tools for investigation of the proteolytic internet

Knockout mice are the gold standard to probe for the role of a specific protease within the interacting network of proteases, substrates, and inhibitors. This proteolytic network, or protease web, determines cell signaling and organ homeostasis. Therefore, protease deficiency or inhibition is intrinsically tied to alterations within this network, always leading to new molecular phenotypes, which define susceptibility of an organ to disease. Furthermore, recent hints, mainly from research on matrix metalloproteinases, about the impact of the protease web on inter-organ signaling molecules suggest the existence of a proteolytic internet of communicating local organ- or molecular polymorphism-specific networks, thereby defining homeostasis and disease susceptibility in the whole organism.

Potential factors of interorgan signals in the development of pancreatitis-associated acute lung injury and acute respiratory distress syndrome

The incidence of the pulmonary complications in patients with acute pancreatitis is up to 60%, from mild hypoxaemia without clinical or radiological abnormalities to severe acute lung injury. Although a number of reviews has described clinical evidence of pancreatitis-associated lung injury (PALI), there is still a lack of information on potential interorgan signalling involved in the development of PALI. The present review discusses the potential factors that have been considered as candidates responsible for interorgan signalling coupling pancreatitis to lung injury. Inflammatory mediators produced from the pancreas, leucocyte system and extrapancreatic organs may directly or indirectly contribute to the high concentration in the circulation, activate circulating leucocytes, initiate the inflammatory responses of pulmonary resident cells or induce acute lung injury. Circulating leucocytes have been suggested to play an important role in interorgan signalling during the development of PALI, by producing ...

AMPK activation increases uncoupling protein-3 expression and mitochondrial enzyme activities in rat muscle without fibre type transitions.

The present study examined the effect of chronic activation of 5'-AMP-activated protein kinase (AMPK) on the metabolic profile, including uncoupling protein-3 (UCP-3) and myosin heavy chain (MHC)-based fibre phenotype of rodent fast-twitch tibialis anterior muscle. Sprague-Dawley rats were given daily injections of 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR), a known activator of AMPK, or vehicle (control) for 28 days. After AICAR treatment, UCP-3 expression at the mRNA level was elevated 1.6 +/- 0.1-fold (P < 0.006) and corresponded to a 3.3 +/- 0.2-fold increase in UCP-3 protein content (P < 0.0001). In addition, the activities of the mitochondrial reference enzymes citrate synthase (EC 4.1.3.7) and 3-hydroxyacyl-CoA-dehydrogenase (EC 1.1.1.35), which are known to increase in proportion to mitochondrial volume density, were elevated 1.6-fold (P < 0.006), while the activity of lactate dehydrogenase (EC 1.1.1.27) was reduced to 80 % of control (P < 0.02). No differences were detected after AICAR treatment in the activities of the glycolytic reference enzymes glyceraldehydephosphate dehydrogenase (EC 1.2.1.12) or phosphofructokinase (EC 2.7.1.11), nor were MHC-based fibre-type transitions observed, using immunohistochemical or electrophoretic analytical methods. These changes could not be attributed to variations in inter-organ signalling by metabolic substrates or insulin. We conclude that an AMPK-dependent pathway of signal transduction does mimic some of the metabolic changes associated with chronic exercise training, but does not affect expression of the MHC-based structural phenotype. Thus, the metabolic and MHC-based fibre types do not appear to be regulated in a co-ordinated way, but may be independently modified by different signalling pathways.

AMPK activation increases uncoupling protein-3 expression and mitochondrial enzyme activities in rat muscle without fibre type transitions

The present study examined the effect of chronic activation of 5′-AMP-activated protein kinase (AMPK) on the metabolic profile, including uncoupling protein-3 (UCP-3) and myosin heavy chain (MHC)-based fibre phenotype of rodent fast-twitch tibialis anterior muscle. Sprague-Dawley rats were given daily injections of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), a known activator of AMPK, or vehicle (control) for 28 days. After AICAR treatment, UCP-3 expression at the mRNA level was elevated 1.6 ± 0.1-fold (P < 0.006) and corresponded to a 3.3 ± 0.2-fold increase in UCP-3 protein content (P < 0.0001). In addition, the activities of the mitochondrial reference enzymes citrate synthase (EC 4.1.3.7) and 3-hydroxyacyl-CoA-dehydrogenase (EC 1.1.1.35), which are known to increase in proportion to mitochondrial volume density, were elevated 1.6-fold (P < 0.006), while the activity of lactate dehydrogenase (EC 1.1.1.27) was reduced to 80 % of control (P < 0.02). No differences were detected after AICAR treatment in the activities of the glycolytic reference enzymes glyceraldehydephosphate dehydrogenase (EC 1.2.1.12) or phosphofructokinase (EC 2.7.1.11), nor were MHC-based fibre-type transitions observed, using immunohistochemical or electrophoretic analytical methods. These changes could not be attributed to variations in inter-organ signalling by metabolic substrates or insulin. We conclude that an AMPK-dependent pathway of signal transduction does mimic some of the metabolic changes associated with chronic exercise training, but does not affect expression of the MHC-based structural phenotype. Thus, the metabolic and MHC-based fibre types do not appear to be regulated in a co-ordinated way, but may be independently modified by different signalling pathways.

Peroxidases in roots and primary leaves of Phaseolus vulgaris Copper and Zinc Phytotoxicity: a comparison

Summary The contribution of peroxidases was studied in roots and primary leaves of bean seedlings as a part of the defence mechanism against copper and zinc imposed oxidative stress. Based on the metal content of the different plant organs, copper was mainly «stored» in the roots, whereas zinc was readily transported to the upper ground parts. In the roots copper had an increasing effect on the capacities of guaiacol and syringaldazine peroxidases. A possible role for lignification in establishing an apoplastic transport barrier in roots is hypothesised. Zinc, on the other hand, had a limited impact on the root metabolism. Future studies should focus on other protection mechanisms in this plant organ. In the primary leaves, both elements had a pronounced (increasing) effect on the peroxidase activities. The data obtained in this study show that peroxidases contribute to the antioxidative defence of the primary leaves of 10 days old bean seedlings after application of both metals and that an interorgan signal transduction pathway is involved. It is pointed out that additional experimental approaches are necessary before the protection mechanism against different metals can be fully compared.

Iron stress-induced changes in root epidermal cell fate are regulated independently from physiological responses to low iron availability.

Iron-overaccumulating mutants were investigated with respect to changes in epidermal cell patterning and root reductase activity in response to iron starvation. In all mutants under investigation, ferric chelate reductase activity was up-regulated both in the presence and absence of iron in the growth medium. The induction of transfer cells in the rhizodermis appeared to be iron regulated in the pea (Pisum sativum L. cv Dippes Gelbe Viktoria and cv Sparkle) mutants bronze and degenerated leaflets, but not in roots of the tomato (Lycopersicon esculentum Mill. cv Bonner Beste) mutant chloronerva, suggesting that in chloronerva iron cannot be recognized by putative sensor proteins. Experiments with split-root plants supports the hypothesis that Fe(III) chelate reductase is regulated by a shoot-borne signal molecule, communicating the iron status of the shoot to the roots. In contrast, the formation of transfer cells was dependent on the local concentration of iron, implying that this shoot signal does not affect their formation. Different repression curves of the two responses imply that the induction of transfer cells occurs after the enhancement of electron transfer across the plasma membrane rather than being causally linked. Similar to transfer cells, the formation of extra root hairs in the Arabidopsis mutant man1 was regulated by the iron concentration of the growth medium and was unaffected by interorgan signaling.

Interorgan Signaling following Pollination in Carnations

Following a compatible pollination in carnation (Dianthus caryophyllus L. `White Sim'), a signal that coordinates postpollination events is translocated from the style to the ovary and petals. In this paper the roles of ethylene and its direct precursor, 1-aminocyclopropane-1-carboxylic acid (ACC), in this signaling were investigated. Following pollination, ethylene and ACC increased sequentially in styles, ovaries, and petals. Ethylene and ACC were highest initially in the stigmatic region of the style but by 24 hours after pollination were highest in the base. Activity of ACC synthase correlated well with ethylene production in styles and petals. In ovaries, ACC synthase activity decreased after pollination despite elevated ethylene production. Lack of ACC synthase activity in pollinated ovaries, coupled with high ACC content, suggests that ACC is translocated within the gynoecium. Further, detection of propylene from petals following application to the ovary provided evidence for movement of ethylene within the flower. Experiments that removed styles and petals at various times after pollination suggest there is a transmissible pollination signal in carnations that has reached the ovary by 12 hours and the petals by 14 to 16 hours.