Origin and Physiological Roles of Inflammation
TL;DR: This work has shown that tissue stress or malfunction induces an adaptive response that is intermediate between the basal homeostatic state and a classic inflammatory response, which is referred to here as para-inflammation.
Abstract: Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.
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TL;DR: The role of PRRs, their signaling pathways, and how they control inflammatory responses are discussed.
6,987 citations
Cites background from "Origin and Physiological Roles of I..."
...Introduction Inflammation is a protective response by the body to ensure removal of detrimental stimuli, as well as a healing process for repairing damaged tissue (Medzhitov, 2008)....
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...Inflammation is a protective response by the body to ensure removal of detrimental stimuli, as well as a healing process for repairing damaged tissue (Medzhitov, 2008)....
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TL;DR: A unifying conceptual framework called “cancer immunoediting,” which integrates the immune system’s dual host-protective and tumor-promoting roles is discussed.
Abstract: Understanding how the immune system affects cancer development and progression has been one of the most challenging questions in immunology. Research over the past two decades has helped explain why the answer to this question has evaded us for so long. We now appreciate that the immune system plays a dual role in cancer: It can not only suppress tumor growth by destroying cancer cells or inhibiting their outgrowth but also promote tumor progression either by selecting for tumor cells that are more fit to survive in an immunocompetent host or by establishing conditions within the tumor microenvironment that facilitate tumor outgrowth. Here, we discuss a unifying conceptual framework called "cancer immunoediting," which integrates the immune system's dual host-protective and tumor-promoting roles.
5,026 citations
TL;DR: Data is reviewed supporting the diverse functional roles carried out by a major class of bacterial metabolites, the short-chain fatty acids (SCFAs), which affect various physiological processes and may contribute to health and disease.
3,363 citations
Cites background from "Origin and Physiological Roles of I..."
...In normal conditions in which commensalhost interaction is nicely balanced, removal of commensals by antibiotics will erase the beneficial effect of SCFAs, contributing to CRC development....
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...Chronic inflammation is a well-established risk factor for colorectal cancer (CRC) (Medzhitov, 2008)....
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...Abbreviations: EEC, enteroendocrine cell; LP, lamina propria; Tregs, regulatory T cells; GLP-1, glucagon like peptide-1; PYY, peptide YY; IBD, inflammatory bowel disease; Teff, effector T cell; DCs, dendritic cells; b-D-OHB, b-D-hydroxybutyrate; CRC, colorectal cancer; VEGF, vascular endothelial growth factor; microbial metabolite-mediated signalinga, signaling through the receptors by microbially produced metabolites (not endogenously produced from the host). propria macrophages (Chang et al., 2014) and differentiation of dendritic cells from bone marrow stem cells (Singh et al., 2010) via HDAC inhibition, making our immune system hyporesponsive to beneficial commensals....
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...Context-Dependent Effects of Microbiota on CRC Depending on the cellular context of the host (i.e., inflammation-driven or acquisition of stemcell-like character), antibiotics and/or SCFAs can function as anti-inflammatory or pro-inflammatory....
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TL;DR: Experimental data demonstrating the role of the microenvironment in metastasis is described, areas for future research are identified and possible new therapeutic avenues are suggested.
Abstract: Metastasis is a multistage process that requires cancer cells to escape from the primary tumour, survive in the circulation, seed at distant sites and grow. Each of these processes involves rate-limiting steps that are influenced by non-malignant cells of the tumour microenvironment. Many of these cells are derived from the bone marrow, particularly the myeloid lineage, and are recruited by cancer cells to enhance their survival, growth, invasion and dissemination. This Review describes experimental data demonstrating the role of the microenvironment in metastasis, identifies areas for future research and suggests possible new therapeutic avenues.
3,332 citations
Cites background from "Origin and Physiological Roles of I..."
...Thus a chronic inflammatory state can quickly set up a cascade of events in which the tumour-promoting effects of immune cells are progressively amplified, often as a by-product of their normal wound-repairing or developmental role...
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TL;DR: The discovery that obesity itself results in an inflammatory state in metabolic tissues ushered in a research field that examines the inflammatory mechanisms in obesity, and metaflammation is summarized, defined as low-grade, chronic inflammation orchestrated by metabolic cells in response to excess nutrients and energy.
Abstract: The modern rise in obesity and its strong association with insulin resistance and type 2 diabetes have elicited interest in the underlying mechanisms of these pathologies. The discovery that obesity itself results in an inflammatory state in metabolic tissues ushered in a research field that examines the inflammatory mechanisms in obesity. Here, we summarize the unique features of this metabolic inflammatory state, termed metaflammation and defined as low-grade, chronic inflammation orchestrated by metabolic cells in response to excess nutrients and energy. We explore the effects of such inflammation in metabolic tissues including adipose, liver, muscle, pancreas, and brain and its contribution to insulin resistance and metabolic dysfunction. Another area in which many unknowns still exist is the origin or mechanism of initiation of inflammatory signaling in obesity. We discuss signals or triggers to the inflammatory response, including the possibility of endoplasmic reticulum stress as an important contributor to metaflammation. Finally, we examine anti-inflammatory therapies for their potential in the treatment of obesity-related insulin resistance and glucose intolerance.
3,045 citations
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TL;DR: Dysfunction of the immune response and metabolic regulation interface can be viewed as a central homeostatic mechanism, dysfunction of which can lead to a cluster of chronic metabolic disorders, particularly obesity, type 2 diabetes and cardiovascular disease.
Abstract: Metabolic and immune systems are among the most fundamental requirements for survival. Many metabolic and immune response pathways or nutrient- and pathogen-sensing systems have been evolutionarily conserved throughout species. As a result, immune response and metabolic regulation are highly integrated and the proper function of each is dependent on the other. This interface can be viewed as a central homeostatic mechanism, dysfunction of which can lead to a cluster of chronic metabolic disorders, particularly obesity, type 2 diabetes and cardiovascular disease. Collectively, these diseases constitute the greatest current threat to global human health and welfare.
7,536 citations
"Origin and Physiological Roles of I..." refers result in this paper
...This idea is in accordance with the fact that many inflammatory mediators (including TNF-α, IL-6, CCL2 and prostaglandins) also have important homeostatic functions, for example in repair of tissues, control of metabolism, and regulation of the hypothalamus–pituitary axi...
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TL;DR: The evidence in favour of alternative macrophage activation by the TH2-type cytokines interleukin-4 (IL-4) and IL-13 is assessed, and its limits and relevance to a range of immune and inflammatory conditions are defined.
Abstract: The classical pathway of interferon-gamma-dependent activation of macrophages by T helper 1 (T(H)1)-type responses is a well-established feature of cellular immunity to infection with intracellular pathogens, such as Mycobacterium tuberculosis and HIV. The concept of an alternative pathway of macrophage activation by the T(H)2-type cytokines interleukin-4 (IL-4) and IL-13 has gained credence in the past decade, to account for a distinctive macrophage phenotype that is consistent with a different role in humoral immunity and repair. In this review, I assess the evidence in favour of alternative macrophage activation in the light of macrophage heterogeneity, and define its limits and relevance to a range of immune and inflammatory conditions.
5,930 citations
"Origin and Physiological Roles of I..." refers background in this paper
...Furthermore, tissue-derived signals can control the activation state and type of recruited macrophag...
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01 Jan 1984
TL;DR: The adaptationist programme is faulted for its failure to distinguish current utility from reasons for origin, and Darwin’s own pluralistic approach to identifying the agents of evolutionary change is supported.
Abstract: An adaptationist programme has dominated evolutionary thought in England and the United States during the past 40 years. It is based on faith in the power of natural selection as an optimizing agent. It proceeds by breaking an organism into unitary ‘traits’ and proposing an adaptive story for each considered separately. Trade-offs among competing selective demands exert the only brake upon perfection; non-optimality is thereby rendered as a result of adaptation as well. We criticize this approach and attempt to reassert a competing notion (long popular in continental Europe) that organisms must be analysed as integrated wholes, with Baupläne so constrained by phyletic heritage, pathways of development and general architecture that the constraints themselves become more interesting and more important in delimiting pathways of change than the selective force that may mediate change when it occurs. We fault the adaptationist programme for its failure to distinguish current utility from reasons for origin (male tyrannosaurs may have used their diminutive front legs to titillate female partners, but this will not explain why they got so small); for its unwillingness to consider alternatives to adaptive stories; for its reliance upon plausibility alone as a criterion for accepting speculative tales; and for its failure to consider adequately such competing themes as random fixation of alleles, production of non-adaptive structures by developmental correlation with selected features (allometry, pleiotropy, material compensation, mechanically forced correlation), the separability of adaptation and selection, multiple adaptive peaks, and current utility as an epiphenomenon of non-adaptive structures. We support Darwin’s own pluralistic approach to identifying the agents of evolutionary change.
5,926 citations
TL;DR: In this paper, the authors criticise the adaptationist program for its inability to distinguish current utility from reasons for origin (male tyrannosaurs may have used their diminutive front legs to titillate female partners, but this will not explain why they got so small).
Abstract: An adaptationist programme has dominated evolutionary thought in England and the United States during the past 40 years. It is based on faith in the power of natural selection as an optimizing agent. It proceeds by breaking an organism into unitary 'traits' and proposing an adaptive story for each considered separately. Trade-offs among competing selective demands exert the onlv brake upon perfection; non-optimality is thereby rendered as a result of adaptation as well. We criticize this approach and attempt to reassert a competing notion (long popular in continental Europe) that organisms must be analysed as integrated wholes, with Bauplane so constrained by phyletic heritage, pathways of development and general architecture that the constraints themselves become more interesting and more important in delimiting pathways of change than the selective force that may mediate change when it occurs. We fault the adaptationist programme for its failure to distinguish current utility from reasons for origin (male tyrannosaurs may have used their diminutive front legs to titillate female partners, but this will not explain why they got so small); for its unwillingness to consider alternatives to adaptive stories; for its reliance upon plausibility alone as a criterion for accepting speculative tales; and for its failure to consider adequately such competing themes as random fixation of alleles, production of nonadaptive structures by developmental correlation with selected features (allometry, pleiotropy, material compensation, mechanically forced correlation), the separability of adaptation and selection, multiple adaptive peaks, and current utility as an epiphenomenon of non-adaptive structures. We support Darwin's own pluralistic approach to identifying the agents of evolutionary change.
5,853 citations
TL;DR: Recent evidence suggests that differential modulation of the chemokine system integrates polarized macrophages in pathways of resistance to, or promotion of, microbial pathogens and tumors, or immunoregulation, tissue repair and remodeling.
5,568 citations
"Origin and Physiological Roles of I..." refers background in this paper
...There are also many other cases in which macrophages are recruited in a tissue-specific or condition-specific manne...
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