Toll-like receptors (TLRs) are discovered as crucial pattern recognition receptors (PRRs) involved in the recognition of pathogen-associated molecular patterns (PAMPs). Later studies showed their ...involvement in the recognition of various damage/danger-associated molecular patterns (DAMPs) generated by host itself. Thus, TLRs are capable of recognizing wide-array of patterns/molecules derived from pathogens and host as well and initiating a proinflammatory immune response through the activation of NF-κB and other transcription factors causing synthesis of proinflammatory molecules. The process of neuroinflammation is seen under both sterile and infectious inflammatory diseases of the central nervous system (CNS) and may lead to the development of neurodegeneration. The present article is designed to highlight the importance of TLRs in the pathogenesis of neuroinflammation under diverse conditions. TLRs are expressed by various immune cells present in CNS along with neurons. However out of thirteen TLRs described in mammals, some are present and active in these cells, while some are absent and are described in detail in main text. The role of various immune cells present in the brain and their role in the pathogenesis of neuroinflammation depending on the type of TLR expressed is described. Thereafter the role of TLRs in bacterial meningitis, viral encephalitis, stroke, Alzheimer's disease (AD), Parkinson's disease (PD), and autoimmune disease including multiple sclerosis (MS) is described. The article is designed for both neuroscientists needing information regarding TLRs in neuroinflammation and TLR biologists or immunologists interested in neuroinflammation.
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•TLRs are crucial PRRs to recognize both intracellular and extracellular PAMPs or DAMPs.•TLRs are also expressed by brain microglia, astrocytes, oligodendrocytes, and neurons.•Activation of TLRs plays a crucial role in generating neuroinflammatory immune response.•Both MyD88-dependent and MyD88-independent TLR signaling pathways generate neuroinflammation.•Neuroinflammation is involved in both sterile (stroke, AD, PD, and MS) and infectious diseases of the brain.
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•Sepsis infects more than 48.9 million people world-wide, with 19.7 million deaths.•Cytokine storm plays a significant role in sepsis, along with severe COVID-19.•TLR signaling ...pathways plays a crucial role in generating the cytokine storm.•Endogenous negative regulators of TLR signaling are crucial to regulate cytokine storm.
Cytokine storm generates during various systemic acute infections, including sepsis and current pandemic called COVID-19 (severe) causing devastating inflammatory conditions, which include multi-organ failure or multi-organ dysfunction syndrome (MODS) and death of the patient. Toll-like receptors (TLRs) are one of the major pattern recognition receptors (PRRs) expressed by immune cells as well as non-immune cells, including neurons, which play a crucial role in generating cytokine storm. They recognize microbial-associated molecular patterns (MAMPs, expressed by pathogens) and damage or death-associate molecular patterns (DAMPs; released and/expressed by damaged/killed host cells). Upon recognition of MAMPs and DAMPs, TLRs activate downstream signaling pathways releasing several pro-inflammatory mediators cytokines, chemokines, interferons, and reactive oxygen and nitrogen species (ROS or RNS), which cause acute inflammation meant to control the pathogen and repair the damage. Induction of an exaggerated response due to genetic makeup of the host and/or persistence of the pathogen due to its evasion mechanisms may lead to severe systemic inflammatory condition called sepsis in response to the generation of cytokine storm and organ dysfunction. The activation of TLR-induced inflammatory response is hardwired to the induction of several negative feedback mechanisms that come into play to conclude the response and maintain immune homeostasis. This state-of-the-art review describes the importance of TLR signaling in the onset of the sepsis-associated cytokine storm and discusses various host-derived endogenous negative regulators of TLR signaling pathways. The subject is very important as there is a vast array of genes and processes implicated in these negative feedback mechanisms. These molecules and mechanisms can be targeted for developing novel therapeutic drugs for cytokine storm-associated diseases, including sepsis, severe COVID-19, and other inflammatory diseases, where TLR-signaling plays a significant role.
Transformations in the marketing function reflect changes in the immediate business environment. While the impact of transformations can be identified through companies' financial results, a deeper ...meaning for such a transformation exists in societal changes. In other words, ongoing changes among consumers, markets, and marketing departments feature prominently in the need for business transformations. Marketing departments too are under increasing pressure to perform. In fact, 80% of chief executive officers do not trust or are unimpressed with their chief marketing officers (CMOs), and CMOs have a high turnover rate. Calls to demonstrate the efficiency of the marketing function have brought the focus on creating value andmanaging customer relationships in a personalized manner.
Sepsis is known since the time (470 BC) of great Greek physician, Hippocrates. Advancement in modern medicine and establishment of separate branches of medical science dealing with sepsis research ...have improved its outcome. However, mortality associated with sepsis still remains higher (25–30%) that further increases to 40–50% in the presence of septic shock. For example, sepsis-associated deaths account more in comparison to deaths-associated with myocardial-infarction and certain cancers (i.e. breast and colorectal cancer). However, it is now well established that profound activation of innate immune cells including macrophages play a very important role in the immunopathogenesis of sepsis. Macrophages are sentinel cells of the innate immune system with their location varying from peripheral blood to various target organs including lungs, liver, brain, kidneys, skin, testes, vascular endothelium etc. Thus, profound and dysregulated activation of these cells during sepsis can directly impact the outcome of sepsis. However, the emergence of the concept of immunometabolism as a major controller of immune response has raised a new hope for identifying new targets for immunomodulatory therapeutic approaches. Thus this present review starts with an introduction of sepsis as a major medical problem worldwide and signifies the role of dysregulated innate immune response including macrophages in its immunopathogenesis. Thereafter, subsequent sections describe changes in immunometabolic stage of macrophages (both M1 and M2) during sepsis. The article ends with the discussion of novel macrophage-specific therapeutic targets targeting their immunometabolism during sepsis and epigenetic regulation of macrophage immunometabolism and vice versa.
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•Sepsis is known to physicians since the time of great Greek Physician Hippocrates (470 BC).•Sepsis still lacks a direct therapeutic approach.•Immunometabolism is well studied in relation of cancer, autoimmunity and other metabolic diseases.•Macrophages are important innate immune cells involved in the pathogenesis of sepsis.•Targeting macrophage immunometabolism may provide novel therapies.
The authors highlight the need for and develop a framework for engagement by reviewing the relevant literature and analyzing popularpress articles. They discuss the definitions of the focal ...constructs—customer engagement (CE) and employee engagement (EE)—in the engagement framework, capture these constructs' multidimensionality, and develop and refine items for measuring CE and EE. They validate the proposed framework with data from 120 companies over two time periods, and they develop strategies to help firms raise their levels of CE and EE to improve performance. They also observe that the influence of EE on CE is moderated by employee empowerment, type of firm (business-to-business B2B vs. business-to-consumer B2C), and nature of industry (manufacturing vs. service); in particular, this effect is stronger for B2B (vs. B2C) firms and service (vs. manufacturing) firms. The authors find that although both CE and EE positively influence firm performance, the effect of CE on firm performance is stronger. Furthermore, the effect of CE and EE on performance is enhanced for B2B (vs. B2C) and for service (vs. manufacturing) firms.
In this study, we highlight the need and develop a framework for customer engagement (CE) by reviewing the marketing literature and analyzing popular press articles. By understanding the evolution of ...customer management, we develop the theory of engagement, arguing that when a relationship is satisfying and has emotional connectedness, the partners become engaged in their concern for each other. As a result, the components of customer engagement include both the direct and the indirect contributions of CE. Based on the theoretical support, our proposed framework elaborates on the components of CE as well as the antecedents (satisfaction and emotion) and consequences (tangible and intangible outcomes) of CE. We also discuss how convenience, nature of the firm (B2B vs. B2C), type of industry (service vs. product), value of the brand (high vs. low), and level of involvement (high vs. low) moderate the link between satisfaction and direct contribution, and between emotions and indirect contribution of CE, respectively. Further, we show how customer engagement can be gained and how firm performance can be maximized by discussing relevant strategies.
Creating Enduring Customer Value Kumar, V.; Reinartz, Werner
Journal of marketing,
11/2016, Letnik:
80, Številka:
6
Journal Article
Recenzirano
One of the most important tasks in marketing is to create and communicate value to customers to drive their satisfaction, loyalty, and profitability. In this study, the authors assume that customer ...value is a dual concept. First, in order to be successful, firms (and the marketing function) have to create perceived value for customers. Toward that end, marketers have to measure customer perceived value and have to provide customer perceptions of value through marketing-mix elements. Second, customers in return give value through multiple forms of engagement (customer lifetime value, in the widest sense) for the organization. Therefore, marketers need to measure and manage this value of the customer(s) to the firm and have to incorporate this aspect into real-time marketing decisions. The authors integrate and synthesize existing findings, show the best practices of implementation, and highlight future research avenues.
Customer value refers to the economic value of the customer's relationship with the firm. This study approaches the topic of customer value for measuring, managing, and maximizing customer ...contributions by proposing a customer valuation theory (CVT) based on economic principles that conceptualizes the generation of value from customers to firms. The author reviews the established economic theories for valuing investor assets (e.g., stocks) and draws a comparison to valuing customer contributions. Furthermore, the author recognizes the differences in the guiding principles between valuing stocks and valuing customers in proposing CVT. Using CVT, the author discusses the concept of customer lifetime value (CLV) as the metric that can provide a reliable, forward-looking estimate of direct customer value. In addition, economic models to estimate CLV, ways to manage CLV using portfolio management principles, and strategies to maximize CLV are discussed in detail. The author extends the customer value concept by discussing ways that a customer can add value to the firm indirectly through incentivized referrals, social media influence, and feedback. Finally, the benefits of CVT to multiple constituencies are offered.
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•Currently no direct target-based therapeutic approach is available for sepsis.•Immunopathogenesis of sepsis also involves an alteration in immune cell metabolism called ...immunometabolism.•T cells are severely affected by sepsis as early as within three hours of onset of sepsis.•Tregs are responsible for the induction of a stage of immunosuppression in the later stage of sepsis.•Targeting T cell and Treg immunometabolism at different stages of sepsis will provide novel therapeutic approaches for sepsis.
Sepsis has always been considered as a big challenge for pharmaceutical companies in terms of discovering and designing new therapeutics. The pathogenesis of sepsis involves aberrant activation of innate immune cells (i.e. macrophages, neutrophils etc.) at early stages. However, a stage of immunosuppression is also observed during sepsis even in the patients who have recovered from it. This stage of immunosuppression is observed due to the loss of conventional (i.e. CD4+, CD8+) T cells, Th17 cells and an upregulation of regulatory T cells (Tregs). This process also impacts metabolic processes controlling immune cell metabolism called immunometabolism. The present review is focused on the T cell-mediated immune response, their immunometabolism and targeting T cell immunometabolism during sepsis as future therapeutic approach. The first part of the manuscripts describes an impact of sepsis on conventional T cells, Th17 cells and Tregs along with their impact on sepsis. The subsequent section further describes the immunometabolism of these cells (CD4+, CD8+, Th17, and Tregs) under normal conditions and during sepsis-induced immunosuppression. The article ends with the therapeutic targeting of T cell immunometabolism (both conventional T cells and Tregs) during sepsis as a future immunomodulatory approach for its management.
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