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The Use of Mouse Models for Understanding the Pathogenesis of Anemia of Inflammation


Iron regulation during times of inflammation is largely driven by the hepcidin-ferroportin axis. Hepcidin expression increases with cytokine activity, particularly IL-6, and causes the internalization and degradation of the transmembrane cellular iron exporter, ferroportin. The impairment of iron efflux into circulation decreases the available supply for erythropoiesis, leading to iron restriction and anemia. Inflammation and increased hepcidin work together to produce the characteristic phenotype of anemia of inflammation (AI): a mild to moderate normocytic anemia with iron restriction, intact iron stores, a shortened erythrocyte lifespan, and depressed erythropoiesis. Evolutionarily, this mechanism limited the availability of iron to microbes during times of infection. However, AI also leads to poor quality of life with increased morbidity and mortality in patients with primary inflammatory conditions.

In this work, we address the need for mouse models of inflammatory anemias. The characterization and manipulation of these models enabled us to elucidate the pathogenesis of AI. Chapter 2 details a mouse model of aging using both wild-type (WT) and genetically manipulated mice. We showed that aging WT mice had increased inflammatory parameters, with hematologic and iron parameters that were consistent with AI. Repeating the model in IL-6 -/- and hepcidin -/- mice demonstrated a partial contribution of IL-6 and hepcidin to the anemia of aging.

Chapter 3 describes four different mouse models of anemia of cancer (AC), with varying degrees of chronicity. Our models displayed a spectrum of anemia severity, and manifested both iron-deficiency and inflammatory anemias. The phenotypes of the different mouse models truly illustrated the heterogeneity of AC cases in human patients. Repeating the experiments in hepcidin -/- mice showed no obvious contribution of hepcidin to AC in our models.

In chapter 4, we extensively characterized a mouse model of acute inflammation using Brucella abortus. We described a model with severe inflammatory anemia, early hepcidin increase, iron-restricted erythropoiesis despite iron accumulation in the liver, shortened erythrocyte lifespan, and suppressed erythropoiesis. With hepcidin ablation, we showed that there was a significant but partial contribution of hepcidin to the development of AI in the Brucella abortus mouse model.

In conclusion, we have characterized mouse models of anemia of aging, anemia of cancer, and anemia of sepsis, in order to elucidate the role of hepcidin and provide a research tool for potential future therapeutics.

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