Established and Emerging Concepts to Treat Imbalances of Iron Homeostasis in Inflammatory Diseases

Abstract

Inflammation, being a hallmark of many chronic diseases, including cancer, inflammatory bowel disease, rheumatoid arthritis, and chronic kidney disease, negatively affects iron homeostasis, leading to iron retention in macrophages of the mononuclear phagocyte system. Functional iron deficiency is the consequence, leading to anemia of inflammation (AI). Iron deficiency, regardless of anemia, has a detrimental impact on quality of life so that treatment is warranted. Therapeutic strategies include (1) resolution of the underlying disease, (2) iron supplementation, and (3) iron redistribution strategies. Deeper insights into the pathophysiology of AI has led to the development of new therapeutics targeting inflammatory cytokines and the introduction of new iron formulations. Moreover, the discovery that the hormone, hepcidin, plays a key regulatory role in AI has stimulated the development of several therapeutic approaches targeting the function of this peptide. Hence, inflammation-driven hepcidin elevation causes iron retention in cells and tissues. Besides pathophysiological concepts and diagnostic approaches for AI, this review discusses current guidelines for iron replacement therapies with special emphasis on benefits, limitations, and unresolved questions concerning oral versus parenteral iron supplementation in chronic inflammatory diseases. Furthermore, the review explores how therapies aiming at curing the disease underlying AI can also affect anemia and discusses emerging hepcidin antagonizing drugs, which are currently under preclinical or clinical investigation.

Prevalence and Predictive Value of Anemia and Dysregulated Iron Homeostasis in Patients with COVID-19 Infection

“…If increased levels of non-transferrin bound iron are found to be associated with tissue damage and a worse outcome, either iron chelators, transferrin or hepcidin agonist may help to reduce iron catalyzed radical formation and cellular damage in organs such as the lung or the vasculature. Furthermore, once the impact of alterations of iron availability on adaptive and innate immune functions as well as on viral pathogenicity and replication have been clarified, therapeutic spatiotemporal alterations of iron availability for either the virus or immune cells may favorably affect the course of the infection and associated pathologic inflammation [24][25][26][27]31]. Nonetheless, both anemia and inflammation-induced disturbances of iron homeostasis are important clinical predictors for risk stratification of SARS-CoV-2-infected patients, thereby improving the clinical management specifically of those at the highest risk [32].…”

The Role of Fibroblast Growth Factor 23 in Inflammation and Anemia

“…Clinically, the etiology of FID has received considerable attention. Pharmaceutical approaches targeting this hepcidin-FPN axis, in regard to correcting inappropriate iron retention and improving systemic iron mobilization, has been the focus of numerous studies [303]. Iron redistribution therapies such as hepcidin neutralizing antibodies, anti-chalins and aptamers have been proven useful and successful in phase I clinical trials to reduce circulating levels of hepcidin [303,304].…”

“…Furthermore, approaches tackling hepcidin-induced internalization of FPN have been subjected to examination. Agents such as FPN stabilizing antibodies have been utilized to block FPN degradation in phase II clinical trials [303,304]. In addition, bone morphogenic protein (BMP) signaling inhibitors specifically for BMP2 and BMP6, along with treatments impacting the severity of inflammation have been employed to inhibit hepcidin synthesis [303,304].…”

Perspectives for the therapy of anemia of chronic diseases

“…HJV.Fc consists of extracellular domain of HJV conjugated with human IgG Fc fragment [10,17]. Currently, other potential drugs, e.g., h5F9.23 and h5F9-AM8, which interact with HJV, are experimentally investigated [18]. Administration of a single dose of ABT-207 or H5F9-AM8 in rats and monkeys resulted in prolonged suppression of hepcidin production and an increase in serum iron concentration [19].…”