Frontiers in Inflammation

Abstract: Inflammation has been recognized as biological phenomena for more than 2000 years by the Roman physician Aulus Cornelius Celcus who described the four cardinal signs of inflammation heat (calor), redness (rubor), pain (dolour), and swelling (tumour), a fifth sign, the loss of function was added later [1]. Consequently, there is ample literature on this subject as illustrated by the fact that more than 500,000 publications on this subject are listed in PubMed. Nevertheless, this volume provides new relevant information on the topic of inflammation, demonstrating that we have not yet complete knowledge on this subject. The reader is directed to extensive introduction of the subject of inflammation [2] as well as many other reports which deals with this subject [3 - 10]. This introductory chapter provides a brief summary of the individual chapter contain in this book.

The acute inflammatory response that occurs due to tissue injury or infection involves multiple cell types with both overlapping and specific functions. The resident mast cell is an important sentinel and able to rapidly release proinflammatory mediators via degranulation. Phagocytic cells, including neutrophils and macrophages, produce cytokines that promote inflammation, but are also important for the clearance of microbes and apoptotic cells. Importantly, macrophages also provide substantial reparative signals to direct the healing process once the inflammatory insult is cleared. Other cells that may mediate acute inflammation include epithelial cells and lymphocytes. This chapter reviews the key functions of these cells in response to an acute insult.

Inflammation is the response of the immune system to injury and infection. As such, it is a critical component of multiple disease states, including anaphylaxis, cancer, cardiovascular disease, obesity, rheumatoid arthritis, diabetes and asthma. Inflammation is a complex process that is composed of multiple stages – the main stages being a pro-inflammatory stage followed by a pro-resolution phase. Eicosanoids and cytokines are critical biochemical mediators involved in both the initiation of the inflammatory response and the resolution of the inflammatory response. Some biochemical mediators are specifically pro-inflammatory or pro-resolution, while others perform both functions. These biochemical mediators play key roles, and thus, the production and inhibition of these mediators are often targets for pharmaceutical intervention.

The skin is a highly complex organ that provides a wide variety of functions, including protection against toxins, pathogenic organisms and physical insults. When there is a breach in this very important barrier, it becomes clear that the skin is also an immune organ. There is a yin and a yang to the role of inflammation in wound healing. Although most of us take it for granted, normal wound healing requires a rapid inflammatory response with quick resolution. When this basic process is disrupted, either due to systemic illness or local factors, pathologic abnormalities in wound healing occur. This chapter will examine the normal inflammatory response as well as the factors that lead to chronic non-healing wounds. Identification of abnormal cellular and molecular immune responses may lead to targeted therapeutic strategies that promote harmony in the wound healing symphony.

Inflammation and the related immune responses are energetically expensive processes, defending against pathogens and maintaining tissue homeostasis. As a result, immune response and metabolic regulation are highly integrated, allowing organisms to adapt to changes in their internal and external environments. Many nutrient- and pathogen-sensing system share common signaling pathways and have been evolutionarily conserved. Studies over the past decade have demonstrated that inflammation is a key feature of obesity, type 2 diabetes, and various cardiovascular disease states. In the context of over nutrition, shifts in tissue metabolism are accompanied with waves of profound recruitment of inflammatory cells (monocytes and lymphocytes) and high proliferation rates among lymphocyte populations. In this chapter, we review recent work addressing metabolic control of inflammation and immunity as well as the molecular aspects of metabolic inflammation converging to insulin resistance. It is crucial to explore the question of causality between the state of chronic inflammation and metabolic dysfunctions seen in obesity, and therefore developing effective therapeutic strategies to cope with the current worldwide obesity epidemic.

Inflammaging is a term referring to the constitutive low-grade inflammation that underlies the process of aging. The causes of inflammaging stem from an upregulation of the innate and a decline in the adaptive immune systems and involve chronic induction of the production of inflammatory mediators, including cytokines, chemokines, and bioactive lipids. Damaged DNA and protein that accumulate in the cells of the aging organisms, oxidative stress, and changes in the function of adipose tissue are among the key culprits leading to the onset of inflammaging. Changes in cytokine signaling pathways at cellular levels also occur with aging, contributing to propagation of inflammation. The inflammaging is considered the main contributing factor to the development of various aging-associated diseases, including cancer, atherosclerosis, metabolic, and neurodegenerative diseases. At least in animal models, inflammaging is subdued by common anti-aging therapies like caloric restriction and resveratrol.

Atopic diseases, including seasonal and perennial allergic rhinitis, asthma, atopic dermatitis, and food allergy, affect a significant proportion of the United States population. Specific host inflammatory patterns characterize these allergic responses. Whether the innate or adaptive immune responses are recruited for a specific antigen, the signature of cytokines secreted will identify this inflammatory pattern and, in the presence of the correct cellular infiltrate, will yield enhanced T helper 2 (Th2), or allergic, inflammation. A description of the various cell types involved in allergic inflammation and the inflammatory responses leading to allergy, including innate and adaptive immunity, are presented in this chapter. Specific pharmacologic modulation utilizing monoclonal antibodies is also discussed.

Accumulating evidence has demonstrated that intensive glucose control improves microvascular complications in type 2 diabetes; however, such interventions have limited value in reducing macrovascular outcomes. Diabetes is in fact a heterogeneous disorder, with subclinical inflammation playing a significant role. An overview of the key inflammatory mediators and signalling pathways driving the onset of diabetes (beta cell failure and insulin resistance) and the development of complications is presented in this chapter. The inflammatory pathways involving interleukins (IL-1β and IL-6), tumour necrosis factor (TNF-α), AGE/RAGE and NLRP3 inflammasome all play important and different roles. Further careful characterisation of these pathways is warranted in order to inform novel lines of therapeutic interventions to reduce the burden of disease. As diabetes affects various target organs, topics covered elsewhere in this book have been deliberately omitted, but the reader is encouraged to read those chapters to gain a more comprehensive picture.

The circulatory system is made up of blood, the heart (a pump) and miles of biologically dynamically involved conduit- the vasculature. The interaction of cellular elements of the blood with the endothelial lining of the vasculature controls so many short and long term inflammatory processes that this system is complex and just now being understood in terms of its cellular biology and biochemistry. Atherosclerosis is the largest killer of persons in developed cultures. The inflammation of atherosclerosis is indicative of the complexity that can occur within the vascular tree. This chapter will examine the dynamic interactions of endothelium, coagulation and inflammation with a focus upon how perturbations of these systems play in creating disease. We will mention a bit about systemic inflammatory autoimmune diseases and note how these create vascular manifestations.

Among a diversity of localizations throughout the human organism, inflammation may also manifest within joints. It is an important feature of rheumatoid and degenerative arthritis, two major rheumatic joint disorders with high individual disease burden and tremendous socio-economic costs. Their etiologies and pathogenic mechanisms are quite diverse. Many aspects are still not fully understood today, and this often compromises instant and adequate individual therapy. However, continuing research efforts seem to succeed in gathering novel insights that also pertain to the inflammatory aspect, which represents a major player in painful and rather disabling joint destruction. However, it turns out to constitute the common final path within a complexity of initiating and perpetuating processes. Even though lacking total completeness, the different contributions of genetics, the immune system and environmental factors are well investigated to a far extent in rheumatoid arthritis, while in degenerative arthritis correlating elucidations lag behind these achievements, which might be due to a minor immunological but the more enigmatic pathology. Nevertheless, growing investigative efforts to similarly distil key mechanisms of disease are also quite well under way in osteoarthritis. The present review aims to give a selected overview over the current knowledge about rheumatoid and degenerative arthritis. Although this includes aspects on disease management in the clinical routine, the main focus is given by shedding light on the etiopathogenic context including establishment of inflammation in both entities.

The oral cavity is a unique anatomical niche with its complex milieu of factors that has developed an intricate and elaborate network of pathophysiological responses. This chapter provides a brief overview of the fundamental pathophysiology of oral cavity with an emphasis on the inflammation and immune responses that regulate various oral diseases. The compounding nature of microbial and mechanical insults adds intriguing facets to the role of inflammation in the etiopathogenesis of oral pathologies. Finally, current and future strategies to prevent, reduce or reverse the injurious nature of inflammation in various oral diseases are briefly discussed.

Inflammatory bowel diseases, Crohn’s disease and ulcerative colitis, are characterized by uncontrolled inflammation of the intestine. Recent advances in the pathogenesis of inflammatory bowel disease have identified over 160 genetic variants conferring risk of disease. Analysis of the intestinal microbiome has also revealed alterations in the diversity in the composition of commensal and pathogenic bacteria. The combined effects of genetic polymorphisms and dysbiosis combine to result in altered activation and regulation of the intestine’s innate immune and adaptive immune systems that result in sustained inflammation. In this review we highlight advances that have elucidated the complex alterations and interactions that shape the inflammatory response of the intestine in the setting of inflammatory bowel disease.

Neuroinflammation is a ubiquitous component of central nervous system (CNS) response to injury. In addition to the disorders traditionally considered inflammatory in nature, neuroinflammation contributes to CNS response in ischemic, traumatic and neurodegenerative disorders. Depending on the particular disorder, both innate and adaptive immune responses may contribute to neuroinflammation. This chapter outlines the basic mechanisms relevant to CNS inflammation. The cells of the CNS innate immune response, including microglia, astrocytes, their mechanisms of activation and innate effector mechanisms such as the production of reactive oxygen and nitrogen species and cytokines are discussed. Features unique to the CNS such as the blood-brain barrier and other mechanisms of CNS immune privilege are outlined. Cells and mechanisms of CNS adaptive immune response such as T lymphocytes, B lymphocytes, activation and effector mechanisms are discussed.

Drugs that dampen acute and chronic inflammation and their sequelae are currently some of the most widely utilised therapeutic agents. With the increasing appreciation that inflammation is involved in the pathobiology of most of the serious and complex disorders that affect mankind, the development and therapeutic uses of anti-inflammatory drugs will likely grow with increasing demand for precision interventions in inflammatory pathways. In this article, we examine commonly utilised anti-inflammatory drugs with a view to how their efficacy has informed our fundamental understanding of inflammatory mediators and pathways. We then look at more recently developed, or developing, targeted strategies that have emerged from a deeper appreciation of these pathways.

Mathematical modeling can be a valuable tool for examining complex biological systems. Modeling can allow researchers to focus on important interactions, identify critical behavior thresholds, explore treatment dosage and timing as well as test new investigational approaches. As will be discussed in this chapter, mathematical modeling has been used to investigate the body’s dynamic response to inflammation within the context of a wide variety of conditions and diseases. We describe a variety of mathematical models that are used to explore inflammation and then enumerate the ways these modeling paradigms have been used to investigate inflammation in specific organs and diseases.

Analysis of normal and pathological behavior of biological systems has greatly benefited from incorporating networks that capture knowledge about interactions among genes, proteins or metabolites into explorations of data from highthroughput techniques such as microarrays, next-generation sequencing, or mass spectrometry. Signaling, metabolic and regulatory networks can help make results from statistical data analysis techniques more interpretable to biologists, and can serve as a regularizing factor narrowing the search space for statistical models that determine differences between different states of biological systems. However, knowledge about the underlying biological networks is still incomplete, with false negatives and false positives, which may affect outcomes of systems biology studies. Thus, results of network modeling need to be critically evaluated by domain experts, and followed by additional experimental or computational validation.