Anemia of inflammation or chronic disease (AICD) is the most common form of anemia in North America outside of iron deficiency (PAS-08-019). Furthermore, the anemia associated with aging and the geriatric syndrome, frailty has recently been linked to inflammation, suggesting the molecular mechanisms underlying both of these anemias may be conserved. Though AICD can arise in diverse clinical contexts, common features of this condition include inflammation and limited erythropoiesis. Hepcidin antimicrobial peptide (Hepc) has been implicated in the pathogenesis of AICD because it is a negative regulator of macrophage iron egress. Though Hepc is sufficient to induce anemia, it is not clear that Hepc is required for the pathogenesis of AICD. Very little is known concerning the molecular regulation of erythropoiesis in the context of inflammation. The slow progress in this area of research is partly related to the heterogeneity of diseases underlying AICD and the difficulty procuring relevant patient samples. To gain insight into the anemia associated with inflammation in the context of chronic disease and aging, we propose to test the hypothesis that IL-6 down regulates hemoglobin synthesis in basophilic erythroblasts, independent of Hepc activity. Animal models provide a critically important tool to characterize the communication between the immune system and erythropoiesis. We have three relevant mouse models that will be useful for investigating the relationship between inflammation, aging, and anemia. Specifically, we aim to: 1.) Determine whether Hepc or IL-6 is required for the anemia associated with inflammation induced by sterile abscess or aging. 2.) Determine whether the expression of genes required for hemoglobin synthesis is inhibited in erythroblasts of aged mice, mice with sterile abscess, and Hepc Tg+ mice. 3.) validate IL-6-mediated inhibition of genes involved in hemoglobin synthesis in vitro. We expect to determine whether Hepc or IL-6 is required for AICD. Further, we expect to identify common regulators of erythropoiesis whose function is modified in the context of aging and inflammation.
This project will gain insight into how the biological processes of inflammation and aging cause anemia in mice. The results of this project will guide our search for improved methods of prevention, detection, and treatment of anemia in humans.
|Atkinson, Meredith A; Kim, Ji Young; Roy, Cindy N et al. (2015) Hepcidin and risk of anemia in CKD: a cross-sectional and longitudinal analysis in the CKiD cohort. Pediatr Nephrol 30:635-43|
|Langdon, Jacqueline M; Yates, Saiah C; Femnou, Laurette K et al. (2014) Hepcidin-dependent and hepcidin-independent regulation of erythropoiesis in a mouse model of anemia of chronic inflammation. Am J Hematol 89:470-9|
|Artz, Andrew S; Xue, Qian-Li; Wickrema, Amittha et al. (2014) Unexplained anaemia in the elderly is characterised by features of low grade inflammation. Br J Haematol 167:286-9|
|McCranor, Bryan J; Kim, Min Jung; Cruz, Nicole M et al. (2014) Interleukin-6 directly impairs the erythroid development of human TF-1 erythroleukemic cells. Blood Cells Mol Dis 52:126-33|
|Petri, Camille R; O'Donnell, Peter H; Cao, Hongyuan et al. (2014) Clofarabine-associated acute kidney injury in patients undergoing hematopoietic stem cell transplant. Leuk Lymphoma 55:2866-73|
|McCranor, Bryan J; Langdon, Jacqueline M; Prince, Olivier D et al. (2013) Investigation of the role of interleukin-6 and hepcidin antimicrobial peptide in the development of anemia with age. Haematologica 98:1633-40|
|Guo, Wen; Bachman, Eric; Li, Michelle et al. (2013) Testosterone administration inhibits hepcidin transcription and is associated with increased iron incorporation into red blood cells. Aging Cell 12:280-91|
|Roy, Cindy N; Semba, Richard D; Sun, Kai et al. (2012) Circulating selenium and carboxymethyl-lysine, an advanced glycation endproduct, are independent predictors of anemia in older community-dwelling adults. Nutrition 28:762-6|
|Chou, David B; Sworder, Brian; Bouladoux, Nicolas et al. (2012) Stromal-derived IL-6 alters the balance of myeloerythroid progenitors during Toxoplasma gondii infection. J Leukoc Biol 92:123-31|
|Merchant, Akil A; Roy, Cindy N (2012) Not so benign haematology: anaemia of the elderly. Br J Haematol 156:173-85|
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