Translational research : the journal of laboratory and clinical medicine
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Review
Molecular and cellular mechanisms linking inflammation to insulin resistance and β-cell dysfunction.
Obesity is a major public health problem worldwide, and it is associated with an increased risk of developing type 2 diabetes. It is now commonly accepted that chronic inflammation associated with obesity induces insulin resistance and β-cell dysfunction in diabetic patients. Obesity-associated inflammation is characterized by increased abundance of macrophages and enhanced production of inflammatory cytokines in adipose tissue. ⋯ High concentrations of glucose or palmitate via the chemokine production promote further immune cell migration and infiltration into the islets. These events ultimately induce inflammatory responses leading to the apoptosis of the pancreatic β cells. In this review, the cellular and molecular players that participate in the regulation of obesity-induced inflammation are discussed, with particular attention being placed on the roles of the molecular players linking inflammation to insulin resistance and β-cell dysfunction.
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Type 1 diabetes mellitus (T1D) is an autoimmune disease often diagnosed in childhood that results in pancreatic β-cell destruction and life-long insulin dependence. T1D susceptibility involves a complex interplay between genetic and environmental factors and has historically been attributed to adaptive immunity, although there is now increasing evidence for a role of innate inflammation. Here, we review studies that define a heightened age-dependent innate inflammatory state in T1D families that is paralleled with high fidelity by the T1D-susceptible biobreeding rat. ⋯ Therapeutic targeting of innate inflammation has been proven effective in preventing and delaying T1D in rat models. Clinical trials of agents that suppress innate inflammation have had more modest success, but efficacy may be improved by the addition of combinatorial approaches that target other aspects of T1D pathogenesis. An understanding of innate inflammation and mechanisms by which this susceptibility is both potentiated and mitigated offers important insight into T1D progression and avenues for therapeutic intervention.
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Review
Interferon regulatory factor 5 in human autoimmunity and murine models of autoimmune disease.
Interferon regulatory factor 5 (IRF5) has been demonstrated as a key transcription factor of the immune system, playing important roles in modulating inflammatory immune responses in numerous cell types including dendritic cells, macrophages, and B cells. As well as driving the expression of type I interferon in antiviral responses, IRF5 is also crucial for driving macrophages toward a proinflammatory phenotype by regulating cytokine and chemokine expression and modulating B-cell maturity and antibody production. This review highlights the functional importance of IRF5 in a disease setting, by discussing polymorphic mutations at the human Irf5 locus that lead to susceptibility to systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease. In concordance with this, we also discuss lessons in IRF5 functionality learned from murine in vivo models of autoimmune disease and inflammation and hypothesize that modulation of IRF5 activity and expression could provide potential therapeutic benefits in the clinic.
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Our Introductory Commentary relates to many topics that are linked to inflammatory responses and how these responses are regulated in order to promote healing of damaged tissues and bring about effective clearance of infectious agents. In non-infectious situations, cells and tissues release products (danger associated molecular patterns) that can trigger damaging inflammatory responses. ⋯ With development of new technologies such as advanced genomic analysis, highly sensitive and sophisticated mass spectrometry and related approaches, as well as the ability to employ mutagenesis induction, we are beginning to define highly sophisticated molecular pathways that previously were opaque. This progress may well have clinical relevance, and we may be on the edge of a scientific revolution in the broad area of inflammation.
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Sickle cell disease (SCD) is a monogenic globin disorder characterized by the production of a structurally abnormal hemoglobin (Hb) variant Hb S, which causes severe hemolytic anemia, episodic painful vaso-occlusion, and ultimately end-organ damage. The primary disease pathophysiology is intracellular Hb S polymerization and consequent sickling of erythrocytes. It has become evident for more than several decades that a more complex disease process contributes to the myriad of clinical complications seen in patients with SCD with inflammation playing a central role. ⋯ In addition, they are useful tools to dissect the molecular and cellular mechanisms that promote individual clinical events and for developing improved therapeutics to address more challenging clinical dilemmas such as refractoriness to opioids or hyperalgesia. Here, we discuss the prospect of targeting multiple inflammatory pathways implicated in the pathogenesis of SCD with a focus on new therapeutics, striving to link the actions of the anti-inflammatory agents to a defined pathobiology, and specific clinical manifestations of SCD. We also review the anti-inflammatory attributes and the cognate inflammatory targets of hydroxyurea, the only Food and Drug Administration-approved drug for SCD.