Investigation of the role of interleukin-6 and hepcidin antimicrobial peptide in the development of anemia with age

Abstract

Anemia is common in older adults and associated with adverse health outcomes in epidemiological studies. A thorough understanding of the complex pathophysiological mechanisms driving anemia in the elderly is lacking; but inflammation, iron restriction, and impaired erythroid maturation are thought to influence the phenotype. We hypothesized that interleukin-6 contributes to this anemia, given its pro-inflammatory activities, its ability to induce hepcidin antimicrobial peptide, and its negative impact on several tissues in older adults. We tested this hypothesis by comparing changes in indices of inflammation, iron metabolism and erythropoiesis in aged C57BL/6 mice to aged mice with targeted deletions of interleukin-6 or hepcidin antimicrobial peptide. Circulating neutrophil and monocyte numbers and inflammatory cytokines increased with age. Decline in hemoglobin concentration and red blood cell number indicated that C57BL/6, interleukin-6 knockout mice, and hepcidin antimicrobial peptide knockout mice all demonstrated impaired erythropoiesis by 24 months. However, the interleukin-6 knock out genotype and the hepcidin antimicrobial peptide knock out genotype resulted in improved erythropoiesis in aged mice. Increased erythropoietic activity in the spleen suggested that the erythroid compartment was stressed in aged C57BL/6 mice compared to aged interleukin-6 knockout mice. Our data suggest C57BL/6 mice are an appropriate mammalian model for the study of anemia with age. Furthermore, although interleukin-6 and hepcidin antimicrobial peptide are not required, they can participate in the development of anemia in aging mice, and could be targeted, pre-clinically, with existing interventions to determine the feasibility of such agents for the treatment of anemia in older adults. ABSTRACTsuch as IL-1α or β.33 Thus, IL-6 and Hepc may have inde

Hepcidin‐dependent and hepcidin‐independent regulation of erythropoiesis in a mouse model of anemia of chronic inflammation

“…Samples were thawed once, then analyzed by the Clinical Research Unit of the Johns Hopkins Institute for Clinical and Translational Research for pro-inflammatory cytokines interferon gamma, IL-1 beta, IL-6, keratinocyte-derived cytokine, and tumor necrosis factor alpha, using multiplex analysis (Meso Scale Discovery, Gaithersburg, MD). This multiplex ELISA reported IL-6 values above background for the IL-6 (−/−) mice, as we have previously reported [25]. We conclude that the ELISA probe may bind to incomplete IL-6 proteins due to the insertion of a stop codon in the middle of the IL-6 gene.…”

“…No IL-6 (+/−) mice were used. The data for untreated IL-6 (−/−) mice, only, also appear in a separate publication developed in parallel with this one [25]. …”

Hepcidin regulation in the anemia of inflammation

“…In a mouse model of anemia of aging [3], older mice exhibited reduced hemoglobin, reduced erythrocyte numbers, increased myeloid lineage cells, and increased IL6 and IFNγ. Although hepcidin was not higher, it may have been inappropriately high relative to the degree of anemia.…”

“…This disorder has been termed anemia of inflammation (AI) or anemia of chronic disease, and is the second most common form of anemia worldwide [1*-2]. A similar condition is seen in the elderly, although often in the absence of a specific underlying disease [3]. Typically, AI is normocytic, normochromic, and mild to moderately severe.…”

Regulation of Iron Metabolism by Hepcidin under Conditions of Inflammation

“…This anemia has been attributed to low grade inflammation; however, the cause of this inflammation is often not explained by infection, CKD, or cancer and has been termed the unexplained anemia of the elderly. Studies in aged mice demonstrate that IL-6 and hepcidin are not directly required for aging-related anemia; however, mice lacking these genes have improved erythropoiesis later in life (89). More recent work has demonstrated that patients with unexplained anemia of the elderly, all of whom have no known history of chronic inflammatory disease, do in fact have features of low grade inflammation including elevated IL-6 expression (90).…”