Summary
Macrophages and neutrophils play a decisive role in host responses to intracellular bacteria including the agent of tuberculosis (TB), Mycobacterium tuberculosis as they represent the ...forefront of innate immune defense against bacterial invaders. At the same time, these phagocytes are also primary targets of intracellular bacteria to be abused as host cells. Their efficacy to contain and eliminate intracellular M. tuberculosis decides whether a patient initially becomes infected or not. However, when the infection becomes chronic or even latent (as in the case of TB) despite development of specific immune activation, phagocytes have also important effector functions. Macrophages have evolved a myriad of defense strategies to combat infection with intracellular bacteria such as M. tuberculosis. These include induction of toxic anti‐microbial effectors such as nitric oxide and reactive oxygen intermediates, the stimulation of microbe intoxication mechanisms via acidification or metal accumulation in the phagolysosome, the restriction of the microbe's access to essential nutrients such as iron, fatty acids, or amino acids, the production of anti‐microbial peptides and cytokines, along with induction of autophagy and efferocytosis to eliminate the pathogen. On the other hand, M. tuberculosis, as a prime example of a well‐adapted facultative intracellular bacterium, has learned during evolution to counter‐balance the host's immune defense strategies to secure survival or multiplication within this otherwise hostile environment. This review provides an overview of innate immune defense of macrophages directed against intracellular bacteria with a focus on M. tuberculosis. Gaining more insights and knowledge into this complex network of host‐pathogen interaction will identify novel target sites of intervention to successfully clear infection at a time of rapidly emerging multi‐resistance of M. tuberculosis against conventional antibiotics.
The most frequent clinical condition exemplifying the interplay between iron and immune function is the anemia of chronic disease (ACD).
Based on a review of the current literature this article ...provides an overview of our current knowledge of iron homeostasis during inflammation, how this contributes to ACD, but also emphasizes pitfalls in diagnosing iron availability and correcting iron deficiency in this setting.
A diversion of iron from the circulation into the reticuloendothelial system and the resutling iron limitation for erythropoiesis are central for the development of ACD. Acute-phase proteins, such as hepcidin, as well as pro- and anti-inflammatory cytokines affect iron acquisition and release pathways of monocytes and macrophages thereby leading to iron restriction within the RES and systemic hypoferremia. These metabolic effects are in part exerted via cytokine-mediated modulation of transcriptional/translational expression of iron metabolism genes or by inducing labile radical formation, which then regulate the posttranscriptional regulation of cellular iron homeostasis. In addition, inflammatory processes affect macrophage iron acquisition via erythrophagocytosis while hepcidin inhibits macrophage iron release via direct interaction with the central iron export protein ferroportin.
Being aware of the effects of iron on cell mediated immune effector function and the central importance of the metal as a nutrient of invading pathogens, iron restriction within the RES harbors potential benefits for the host and may serve as a defense strategy of the body. Therapeutic manipulation of iron balance and transport under inflammatory conditions is thus a major challenge harboring both, putative beneficial and detrimental effects.
Microbes exert a major impact on human health and disease by either promoting or disrupting homeostasis, in the latter instance leading to the development of infectious diseases. Such disparate ...outcomes are driven by the ever‐evolving genetic diversity of microbes and the countervailing host responses that minimize their pathogenic impact. Host defense strategies that limit microbial pathogenicity include resistance mechanisms that exert a negative impact on microbes, and disease tolerance mechanisms that sustain host homeostasis without interfering directly with microbes. While genetically distinct, these host defense strategies are functionally integrated, via mechanisms that remain incompletely defined. Here, we explore the general principles via which host adaptive responses regulating iron (Fe) metabolism impact on resistance and disease tolerance to infection.
This review analyzes the regulation of host iron metabolism in response to infection with a focus on pathogen class‐specific mechanisms. Strategies to target Fe/heme metabolism for the treatment of infectious diseases are also discussed.
Lipid and immune pathways are crucial in the pathophysiology of metabolic and cardiovascular disease. Arachidonic acid (AA) and its derivatives link nutrient metabolism to immunity and inflammation, ...thus holding a key role in the emergence and progression of frequent diseases such as obesity, diabetes, non-alcoholic fatty liver disease, and cardiovascular disease. We herein present a synopsis of AA metabolism in human health, tissue homeostasis, and immunity, and explore the role of the AA metabolome in diverse pathophysiological conditions and diseases.
Anemia is very common in patients with inflammatory disorders. Its prevalence is associated with severity of the underlying disease, and it negatively affects quality of life and cardio-vascular ...performance of patients. Anemia of inflammation (AI) is caused by disturbances of iron metabolism resulting in iron retention within macrophages, a reduced erythrocyte half-life, and cytokine mediated inhibition of erythropoietin function and erythroid progenitor cell differentiation. AI is mostly mild to moderate, normochromic and normocytic, and characterized by low circulating iron, but normal and increased levels of the storage protein ferritin and the iron hormone hepcidin. The primary therapeutic approach for AI is treatment of the underlying inflammatory disease which mostly results in normalization of hemoglobin levels over time unless other pathologies such as vitamin deficiencies, true iron deficiency on the basis of bleeding episodes, or renal insufficiency are present. If the underlying disease and/or anemia are not resolved, iron supplementation therapy and/or treatment with erythropoietin stimulating agents may be considered whereas blood transfusions are an emergency treatment for life-threatening anemia. New treatments with hepcidin-modifying strategies and stabilizers of hypoxia inducible factors emerge but their therapeutic efficacy for treatment of AI in ill patients needs to be evaluated in clinical trials.
Anaemia is frequently observed in patients with inflammatory rheumatic diseases. Depending on its severity, anaemia negatively affects cardiovascular performance, physical activity and the quality of ...life of patients. However, anaemia is considered to be a symptom of the underlying inflammatory disease and, thus, neglected as a complex medical condition that warrants specific diagnosis and treatment. Although inflammation-induced alterations in iron homeostasis and erythropoiesis have a dominant role in the pathogenesis of this type of anaemia, multiple other factors such as chronic blood loss, haemolysis, disease and treatment-associated adverse effects or vitamin deficiencies can also take part in the development of anaemia. Accordingly, the prevalence of anaemia is positively associated with the severity of the underlying disease. This Review will summarize epidemiological data on anaemia in inflammatory rheumatic diseases, along with a detailed description of underlying pathophysiological pathways, available diagnostic tools and practical diagnostic strategies. Discussion of established and newly emerging treatment regimens, as well as the need for further research in this clinically relevant field, will also be included.
Iron metabolism and tumor biology are intimately linked. Iron facilitates the production of oxygen radicals, which may either result in iron-induced cell death, ferroptosis, or contribute to ...mutagenicity and malignant transformation. Once transformed, malignant cells require high amounts of iron for proliferation. In addition, iron has multiple regulatory effects on the immune system, thus affecting tumor surveillance by immune cells. For these reasons, inconsiderate iron supplementation in cancer patients has the potential of worsening disease course and outcome. On the other hand, chronic immune activation in the setting of malignancy alters systemic iron homeostasis and directs iron fluxes into myeloid cells. While this response aims at withdrawing iron from tumor cells, it may impair the effector functions of tumor-associated macrophages and will result in iron-restricted erythropoiesis and the development of anemia, subsequently. This review summarizes our current knowledge of the interconnections of iron homeostasis with cancer biology, discusses current clinical controversies in the treatment of anemia of cancer and focuses on the potential roles of iron in the solid tumor microenvironment, also speculating on yet unknown molecular mechanisms.
The novel Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) is a global health concern. Vitamin D (VITD) deficiency has been suggested to ...alter SARS-CoV-2 susceptibility and the course of disease. Thus, we aimed to investigate associations of VITD status to disease presentation within the CovILD registry. This prospective, multicenter, observational study on long-term sequelae includes patients with COVID-19 after hospitalization or outpatients with persistent symptoms. Eight weeks after PCR confirmed diagnosis, a detailed questionnaire, a clinical examination, and laboratory testing, including VITD status, were evaluated. Furthermore, available laboratory specimens close to hospital admission were used to retrospectively analyze 25-hydroxyvitamin D levels at disease onset. A total of 109 patients were included in the analysis (60% males, 40% females), aged 58 ± 14 years. Eight weeks after the onset of COVID-19, a high proportion of patients presented with impaired VITD metabolism and elevated parathyroid hormone (PTH) levels. PTH concentrations were increased in patients who needed intensive care unit (ICU) treatment, while VITD levels were not significantly different between disease severity groups. Low VITD levels at disease onset or at eight-week follow-up were not related to persistent symptom burden, lung function impairment, ongoing inflammation, or more severe CT abnormalities. VITD deficiency is frequent among COVID-19 patients but not associated with disease outcomes. However, individuals with severe disease display a disturbed parathyroid-vitamin-D axis within their recovery phase. The proposed significance of VITD supplementation in the clinical management of COVID-19 remains elusive.
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