Cytokine and Lipid Mediator Regulation of Group 2 Innate Lymphoid Cells (ILC2s) in Human Allergic Airway Disease.

The recent discovery of group 2 innate lymphoid cells (ILC2s) has caused a paradigm shift in the understanding of allergic airway disease pathogenesis. Prior to the discovery of ILC2s, Th2 cells were largely thought to be the primary source of type 2 cytokines; however, activated ILC2s have since been shown to contribute significantly, and in some cases, dominantly to type 2 cytokine production. Since the discovery of ILC2s in 2010, many mediators have been shown to regulate their effector functions. Initial studies identified the epithelial derived cytokines IL-25, IL-33, and TSLP as activators of ILC2s, and recent studies have identified many additional cytokine and lipid mediators that are involved in ILC2 regulation. ILC2s and their mediators represent novel therapeutic targets for allergic airway diseases and intensive investigation is underway to better understand ILC2 biology and upstream and downstream pathways that lead to ILC2-driven airway pathology. In this review, we will focus on the cytokine and lipid mediators that regulate ILC2s in human allergic airway disease, as well as highlight newly discovered mediators of mouse ILC2s that may eventually translate to humans

Quantifying the relevance of different mediators in the human immune cell network

Immune cells coordinate their efforts for the correct and efficient functioning of the immune system (IS). Each cell type plays a distinct role and communicates with other cell types through mediators such as cytokines, chemokines and hormones, among others, that are crucial for the functioning of the IS and its fine tuning. Nevertheless, a quantitative analysis of the topological properties of an immunological network involving this complex interchange of mediators among immune cells is still lacking. Here we present a method for quantifying the relevance of different mediators in the immune network, which exploits a definition of centrality based on the concept of efficient communication. The analysis, applied to the human immune system, indicates that its mediators significantly differ in their network relevance. We found that cytokines involved in innate immunity and inflammation and some hormones rank highest in the network, revealing that the most prominent mediators of the IS are molecules involved in these ancestral types of defence mechanisms highly integrated with the adaptive immune response, and at the interplay among the nervous, the endocrine and the immune systems.Comment: 10 pages, 3 figure

Driving chronicity in rheumatoid arthritis: perpetuating role of myeloid cells

Acute inflammation is a complex and tightly regulated homeostatic process that includes leukocyte migration from the vasculature into tissues to eliminate the pathogen/injury, followed by a pro-resolving response promoting tissue repair. However, if inflammation is uncontrolled as in chronic diseases such as Rheumatoid Arthritis (RA) it leads to tissue damage and disability. Synovial tissue inflammation in RA patients is maintained by sustained activation of multiple inflammatory positive-feedback regulatory pathways in a variety of cells including myeloid cells. In this review, we will highlight recent evidence uncovering biological mechanisms contributing to the aberrant activation of myeloid cells that contributes to perpetuation of inflammation in RA, and discuss emerging data on anti-inflammatory mediators contributing to sustained remission that may inform a novel category of therapeutic targets

Lipid Mediators in Inflammation

Lipids are potent signaling molecules that regulate a multitude of cellular responses, including cell growth and death and inflammation/infection, via receptor-mediated pathways. Derived from polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), each lipid displays unique properties, thus making their role in inflammation distinct from that of other lipids derived from the same PUFA. This diversity arises from their synthesis, which occurs via discrete enzymatic pathways and because they elicit responses via different receptors. This review will collate the bioactive lipid research to date and summarize the major pathways involved in their biosynthesis and role in inflammation. Specifically, lipids derived from AA (prostanoids, leukotrienes, 5-oxo-6,8,11,14-eicosatetraenoic acid, lipoxins, and epoxyeicosatrienoic acids), EPA (E-series resolvins), and DHA (D-series resolvins, protectins, and maresins) will be discussed herein

Exosomes: Versatile Nano Mediators of Immune Regulation.

One of many types of extracellular vesicles (EVs), exosomes are nanovesicle structures that are released by almost all living cells that can perform a wide range of critical biological functions. Exosomes play important roles in both normal and pathological conditions by regulating cell-cell communication in cancer, angiogenesis, cellular differentiation, osteogenesis, and inflammation. Exosomes are stable in vivo and they can regulate biological processes by transferring lipids, proteins, nucleic acids, and even entire signaling pathways through the circulation to cells at distal sites. Recent advances in the identification, production, and purification of exosomes have created opportunities to exploit these structures as novel drug delivery systems, modulators of cell signaling, mediators of antigen presentation, as well as biological targeting agents and diagnostic tools in cancer therapy. This review will examine the functions of immunocyte-derived exosomes and their roles in the immune response under physiological and pathological conditions. The use of immunocyte exosomes in immunotherapy and vaccine development is discussed

Beyond Cholinesterase Inhibition. Anti-Inflammatory Role and Pharmacological Profile of Current Drug Therapy for Alzheimer's Disease

Inflammation is a common response of an individual against either exogenous or endogenous damage. The role of inflammation and of inflammatory cells recently emerged also in the pathogenesis of neurodegenerative disorders. Experimental evidences show how neurotransmitters, besides their role in the synapses, play a modulatory role during immune response. Drugs used for treatment of dementia symptoms are able to increase neurotransmitters levels, and likely to have a modulatory role during immune response. Aim of this review is to discuss the most recent advances on inflammation role during neurodegeneration and also to individuate the potential anti-inflammatory role played by drugs currently used for Alzheimer's disease treatment

An Inflammation-Centric View of Neurological Disease: Beyond the Neuron

Inflammation is a complex biological response fundamental to how the body deals with injury and infection to eliminate the initial cause of cell injury and effect repair. Unlike a normally beneficial acute inflammatory response, chronic inflammation can lead to tissue damage and ultimately its destruction, and often results from an inappropriate immune response. Inflammation in the nervous system ("neuroinflammation"), especially when prolonged, can be particularly injurious. While inflammation per se may not cause disease, it contributes importantly to disease pathogenesis across both the peripheral (neuropathic pain, fibromyalgia) and central [e.g., Alzheimer disease, Parkinson disease, multiple sclerosis, motor neuron disease, ischemia and traumatic brain injury, depression, and autism spectrum disorder] nervous systems. The existence of extensive lines of communication between the nervous system and immune system represents a fundamental principle underlying neuroinflammation. Immune cell-derived inflammatory molecules are critical for regulation of host responses to inflammation. Although these mediators can originate from various non-neuronal cells, important sources in the above neuropathologies appear to be microglia and mast cells, together with astrocytes and possibly also oligodendrocytes. Understanding neuroinflammation also requires an appreciation that non-neuronal cell-cell interactions, between both glia and mast cells and glia themselves, are an integral part of the inflammation process. Within this context the mast cell occupies a key niche in orchestrating the inflammatory process, from initiation to prolongation. This review will describe the current state of knowledge concerning the biology of neuroinflammation, emphasizing mast cell-glia and glia-glia interactions, then conclude with a consideration of how a cell's endogenousmechanisms might be leveraged to provide a therapeutic strategy to target neuroinflammation

Combined In Silico, In Vivo, and In Vitro Studies Shed Insights into the Acute Inflammatory Response in Middle-Aged Mice

We combined in silico, in vivo, and in vitro studies to gain insights into age-dependent changes in acute inflammation in response to bacterial endotoxin (LPS). Time-course cytokine, chemokine, and NO2-/NO3- data from "middle-aged" (6-8 months old) C57BL/6 mice were used to re-parameterize a mechanistic mathematical model of acute inflammation originally calibrated for "young" (2-3 months old) mice. These studies suggested that macrophages from middle-aged mice are more susceptible to cell death, as well as producing higher levels of pro-inflammatory cytokines, vs. macrophages from young mice. In support of the in silico-derived hypotheses, resident peritoneal cells from endotoxemic middle-aged mice exhibited reduced viability and produced elevated levels of TNF-α, IL-6, IL-10, and KC/CXCL1 as compared to cells from young mice. Our studies demonstrate the utility of a combined in silico, in vivo, and in vitro approach to the study of acute inflammation in shock states, and suggest hypotheses with regard to the changes in the cytokine milieu that accompany aging. © 2013 Namas et al

SAR Studies on the Inhibitors for the Treatment of Inflammatory Diseases

School of Molecular Sciences(Chemistry)Inflammation is defensive host response that occurs from infection and injury and the inflammatory process is the pivotal physiological response of our body and essential part of the human physiology. Due to the mechanistic relationship between chronic diseases and inflammation, a better understanding for the molecular mechanism of chronic inflammation could attenuate cellular inflammation pathways. Under inflammatory pathways, the impetus of proinflammatory mediators usually caused by the increased expression of transcriptional factors which is also a potential targets in the development of novel and effective anti-inflammatory therapeutics. Among others, we are interested in the Nuclear Factor Kappa-B (NF-??B) which is reported as a major mediator that regulates inflammatory gene expression and also decrease the prevalence of inflammation responses. To suppress the inflammatory activity, inhibitors that could selectively target this protein are needed. We therefore, chose the natural product cerulenin which has been studied widely because of its antifungal and antibacterial properties, for designing inhibitors. In light of the interesting inhibitory properties displayed by cerulenin for fatty acid synthase (FASN), we were keen to explore the possible binding mode of this natural product with a view to design various derivatives that would be amicable to synthetic manipulation in order to enable SAR studies. Potent analogues of cerulenin, with various chain lengths and substitutions, are synthesized and evaluated for their ability to inhibit NF-??B enhanceosome. Taken together, by identifying target protein with constructed inhibitors derived from cerulenin might give revolutionary effect on discovering new therapeutic agents.ope