Mechanisms of interorgan crosstalk in health and disease

Abstract

The development of multicellularity of organisms during evolution brought about the need for coordinated activity of different cell types and organs in order to adapt to changing external and internal microenvironmental conditions. The concept of a 'milieu interieur' that requires stabilization to keep the organism in balance was first put forward by the 19th century French physiologist Claude Bernard (1813–1873), who proposed that chemical messengers are exchanged between organs in order to maintain the 'milieu interieur' [[1]]. The term hormone, which describes some of those chemical messengers, was coined much later by the British physiologist Ernest Starling (1866–1927) based on work on pancreatic secretion [[2, 3]]. The word hormone derives from Greek and means 'to arouse or excite', and Starling described hormones as 'the chemical messengers which speeding from cell to cell along the blood stream, may coordinate the activities and growth of different parts of the body'. Building on work of Bernard, Starling and others, Walter B. Cannon (1871–1945) of Harvard Medical School in Boston, USA, first used the term 'homeostasis' in his seminal 1929 review on the role that interorgan communication plays in this process [[4]]. The 'Cori cycle' described by Carl Cori (1896–1984) and Gerty Cori (1896–1957) of Washington University in St. Louis, USA, who were awarded the Nobel Prize for this discovery in 1947, represents one of the first descriptions of an efficient interorgan communication system that facilitates metabolic adaptation to energy demands by allowing lactate produced by anaerobic glycolysis in muscles to be recycled and converted to glucose by the liver [[5]]. Since these pioneering studies, our knowledge of interorgan crosstalk mediators and mechanisms that act in an autocrine, paracrine, or in particular, endocrine manner to regulate homeostasis has grown substantially. For example, key metabolic hormones released by the pancreas, such as insulin and glucagon, were identified and adopted as therapeutics during the 20th century, and many signaling molecules involved in the regulation of metabolic homeostasis released for example from the liver (hepatokines) [[6]], muscle (myokines) [[7, 8]], or fat cells (adipokines/batokines) [[9]] have been added to our arsenal of potential therapeutics or therapeutic targets in recent decades. Many of these molecules are indeed involved in interorgan communication during normal physiology, for example from gut to brain [[10]], muscle to various organs including brain, adipose tissue, bone, liver, gut, pancreas, vascular bed and skin [[8, 11, 12]], or connect the cardiovascular system, brain, lymphoid organs, the gut microbiome, and the kidney [[13-16]]. In addition, interorgan communication is altered in many pathological conditions, for instance obesity, diabetes, cardiovascular disease, or kidney disease, which are now viewed as multiorgan diseases. In fact, acute or chronic injury in one organ/tissue often causes secondary remote organ complications, which drive most of the morbidity and mortality in these diseases. As examples, acute kidney injury can trigger remote organ complications such as acute lung injury [[17-19]], cardiovascular dysfunction [[20]], or hepatic and intestinal dysfunction [[21]], while direct lung injury, for example by infection, can cause kidney failure [[22-25]]. As such, understanding the molecular details of interorgan communication is a necessary prerequisite to develop novel therapeutics that address maladaptive interorgan dependencies and secondary organ complications. Beyond hormones and metabolites that travel from organ to organ via the circulation, new avenues of interorgan communication have been discovered. In particular, neuroimmune interactions maintain tissue homeostasis and protection, and involve the brain and peripheral nervous system (somatic or autonomous), which anatomically links various organs [[26]]. In addition, exosomes are now recognized as important vehicles of interorgan communication mediators in health and disease states [[27-32]]. Further, structural tissues not traditionally thought of as hormone-producing, such as bone, are gaining importance as endocrine organs in interorgan crosstalk [[12]]. Beyond omics technologies that have significantly advanced our ability to understand cellular complexity and function, new technologies can now help us understand interorgan crosstalk in vitro, including microphysiological systems that connect various organ model systems in a 'dish' while reducing biological complexity [[33-35]]. The field of interorgan crosstalk research is rapidly expanding, and in 2022 FEBS and EMBO will feature the first two conferences on the topic. The EMBO/EMBL virtual symposium 'Interorgan communication in health and disease' (https://www.embl.org/about/info/course-and-conference-office/events/ees22-02/) in Heidelberg, Germany, 21–23 March, 2022, and the FEBS/EMBO Lecture Course 'Mechanisms of Interorgan Crosstalk in Health and Disease' on the Island of Spetses, Greece, May 19–27, 2022 (https://meetings.embo.org/event/21-molecular-mechanisms). The latter will bring together young scientists (PhD students and postdocs) and many of the authors in this FEBS Letters Special Issue, which serves as an introductory feature to the Lecture Course. The FEBS Letters Special Issue 'Mechanisms of Interorgan Crosstalk in Health and Disease' provides an overview of novel findings in interorgan crosstalk and brings together perspectives of experts from various different fields of investigation. This collection consists of 10 reviews and has three focal points, as follows: The first focus is on inflammatory mediators in interorgan crosstalk. Systemic inflammatory disorders (SIDs) comprise a broad range of diseases characterized by dysregulated excessive innate immune responses. Severe forms of SIDs can lead to organ failure and death, and their increasing incidence represents a major burden for the healthcare system. Protease-mediated ectodomain shedding of cytokines and their receptors constitute a central regulatory mechanism of these inflammatory responses. The metalloprotease A disintegrin and metalloproteinase (ADAM) 17 is the best-characterized ectodomain sheddase capable of releasing tumor-necrosis-factor (TNF), its receptors (TNFR1/2), ligands of the epidermal growth factor receptor, and soluble interleukin-6 (IL-6) receptor, which are decisive factors in systemic inflammation. Yet, other proteases such as meprins also play an important role: In this context, Sascha Rahn and Christoph Becker-Pauly are contributing an important overview of the role of 'Meprin and ADAM proteases as triggers of systemic inflammation' [[36]]. IL-6 is an inflammatory cytokine, the level of which is highly elevated in most, if not all, inflammatory states. IL-6 triggers cell type-specific responses and acts on target cells via a specific interleukin-6 receptor (IL-6R), which, together with IL-6, binds to and induces the dimerization of a second receptor subunit, gp130. IL-6 also binds to soluble IL-6R, and this complex interacts with ubiquitously expressed gp130, regardless of IL-6R expression. This allows cells that do not express IL-6R and would be otherwise insensitive to IL-6 to respond to it. Stefan Rose-John summarizes current concepts and state-of-the-art approaches to study local and systemic activities of this important cytokine in the review article entitled 'Local and systemic effects of IL-6 in inflammation and cancer' [[37]]. David Millrine, Robert H. Jenkins, Stuart T. O. Hughes and Simon A. Jones in their review 'Making sense of IL-6 signalling cues in pathophysiology' [[38]] will deepen our understanding of the signaling networks that shape the way cells sense and interpret cytokine cues. With an emphasis on IL-6 biology, they will highlight the importance of these mechanisms to both physiological processes and pathophysiological outcomes. Eirini Kefalogianni's manuscript 'Soluble forms of cytokine and growth factor receptors: Mechanisms of generation and modes of action in the regulation of local and systemic inflammation' provides a state-of-the-art review of the role of soluble receptors in inflammation, their modes of generation, and local and systemic action [[39]]. Her review highlights that such receptors are not only released by cleavage from the cell surface (as is the case for IL-6-R), but also via secretion of soluble receptor isoforms, as well as by their inclusion in exosomes. Interestingly, these soluble receptors can exert their functions as decoy receptors, competing for ligand binding with the respective membrane-bound forms resulting in reduced signaling, but they can also stabilize their ligands or activate additional signaling events through interactions with other proteins on the cell surface. As such, they significantly expand the complexity of cytokine signaling and contribute to their systemic effects on organs far away from their site of release. Finally, in their review 'Interorgan crosstalk in pancreatic islet function and pathology' [[40]], Ron Evans and Zong Wei will discuss recent advances in interorgan communication from the metabolic, immune and neural system to pancreatic islets, their biological implication in normal pancreas endocrine function, and their role in the (mal)adaptive responses of pancreatic islets to nutrition-induced stress. The second focal point of the Special Issue is the role of intercellular and interorgan crosstalk after acute or chronic tissue injury. Remote organ inflammation after for example kidney injury or heart injury are critical drivers of deadly secondary organ complications. Andreas Herrlich's review 'Interorgan crosstalk mechanisms in disease: the case of acute kidney injury-induced remote lung injury' [[41]] highlights the role of kidney-released mediators that cause lung endothelial leakage, lung edema, lung inflammation, and respiratory failure as one important example of such clinically important crosstalk. Luka Nicin, Julian U G Wagner, Guillermo Luxán and Stefanie Dimmeler's review 'Fibroblast-mediated intercellular crosstalk in the healthy and diseased heart' [[42]] reports current knowledge of cellular interactions in the healthy, diseased, and aging heart and their potential relevance for interorgan crosstalk. The third but equally important focus is on newly described modes of interorgan crosstalk, tissues not normally thought of as endocrine organs and new developments in the modeling of interorgan crosstalk in vitro. Julia Bischoff, Alexander Schultz and Helen Morrison provide a state-of-the-art review on 'The role of exosomes in intercellular and interorgan communication of the peripheral nervous system' [[43]]. Julian Meyer Berger and Gerard Karsenty illuminate bone as an endocrine organ involved in interorgan communication in their review 'Osteocalcin and the Physiology of Danger' [[44]]. Finally, Martin Trapecar discusses emerging technologies and reductionist in vitro systems mimicking human physiology that promise to provide clarity in systemic metabolic and inflammatory diseases in his review 'Multiorgan microphysiological systems as tools to interrogate interorgan crosstalk and complex diseases' [[45]]. In summary, insights into mechanisms of interorgan crosstalk in disease and its mediators are critical for the understanding of the regulation of homeostasis, as well as the biology of complex multiorgan diseases. Given the broad importance of interorgan crosstalk in the bodily response to acute or chronic tissue injury, it does not come as a surprise that interorgan crosstalk contributes also to many age-related degenerative disorders. Therefore, interorgan crosstalk research will be central to our efforts to understand organismal homeostasis and pathologic processes involved in aging, as well as the development of therapeutics, and will remain so for years to come. Andreas Herrlich—Associate Professor and Director of Translational Research in the Division of Nephrology at Washington University School of Medicine in St. Louis, MO, USA. His laboratory is focused on interorgan crosstalk in the context of acute or chronic tissue injury, in particular between the kidney, heart, lung and brain. He recently identified a novel kidney-released mediator, osteopontin, that causes remote lung injury and respiratory failure. Andreas Herrlich obtained his MD and PhD in Molecular Biology from the Freie Universitaet Berlin, Germany where he worked with Guenther Schultz and Thomas Gudermann. He completed training in Internal medicine and was a chief resident at Johns Hopkins Bayview Medical Center, Baltimore, USA, 1998–2002. From 2002 to 2006, he trained in Nephrology at Massachusetts General Hospital and Brigham and Women's Hospital in Boston, USA. From 2003 to 2010, he did postdoctoral work in the laboratory of Harvey Lodish at the Whitehead Institute for Biomedical Research, Cambridge, USA. He became Assistant Professor of Medicine at Harvard Medical School, Boston, USA, in 2010, and moved to Washington University School of Medicine in St. Louis, USA, in 2016, where he is a tenured Associate Professor of Medicine. Eirini Kefaloyianni—Assistant Professor in the Division of Rheumatology at Washington University School of Medicine in St. Louis, MO, USA. Her laboratory studies mechanisms of cellular communication, in particular the release of growth factors, cytokines and their soluble receptors, in tissue injury, inflammation and fibrosis. Her work has uncovered critical mediators in kidney disease progression, including ligands of the epidermal growth factor family and cytokines, which are released by proximal tubule cells of the kidney after injury and drive persistent inflammation and fibrosis. Eirini Kefaloyianni obtained her PhD at the University of Athens in Greece, followed by postdoctoral research at New York University and then at Harvard Medical School and Brigham and Women's Hospital in Boston, USA. She was recruited to Washington University in St. Louis in 2016. She is the current recipient of an American Heart Association Career Development Award and also of the American Society of Nephrology Career Development 'Gottschalk Award'. Stefan Rose-John—Professor and Director of the Institute of Biochemistry at the University of Kiel Medical School in Kiel, Germany. His group established the paradigm of IL-6 trans‑signaling via the ADAM17 metalloprotease-released soluble IL-6 receptor, which represents the major pro-inflammatory pathway of IL-6 signaling. He designed the protein sgp130Fc (Olamkicept), which specifically blocks IL-6 trans‑signaling without interfering with protective and regenerative signaling via the membrane-bound IL-6R. Olamkicept will enter phase III clinical trials in patients with inflammatory bowel disease in 2022. Stefan Rose-John obtained his Doctoral degree in Biological Sciences at the University of Heidelberg, Germany. After a postdoc in Michigan, USA, he returned to Heidelberg to join the Institute of Biochemistry at the German Cancer Research Center. He obtained his Habilitation in Biochemistry at RWTH Aachen, Germany in 1992 and became Associate Professor at the University of Mainz, Germany, in 1994 before moving to Kiel, Germany, in 2000.

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