The pathophysiology of ACI is multifactorial, resulting from the effects of inflammatory cytokines, particularly interleukin-1 (IL-1), IL-6, IL-10, tumor necrosis factor-α (TNF-α), interferon-γ (IFN γ), IFN-α, and IFN-β, all or some of which are increased in most inflammatory processes, i.e., infections, autoimmune disorders, and malignancies. Cytokine levels frequently correlate inversely with hemoglobin, potentially implicating them in the etiology of ACI. Serum TNF-α levels correlate with both disease activity and the degree of anemia in RA. Transgenic mice with endogenously elevated IFN-γ exhibit preferential differentiation of non-erythroid lineage hematopoietic precursors and diminished erythroid burst-forming units (BFU-E). Furthermore, multiple clinical trials using cytokine antagonists in inflammatory diseases demonstrate effective reversal of anemia. For example, in patients with Crohn disease, anti-TNF-α therapy improved both disease activity and anemia. Anti-TNF-α therapy in vitro increased the growth of peripheral blood-derived erythroid progenitors from patients with active disease. Multiple lines of evidence suggest that elevated inflammatory cytokines lead to (1) decreased RBC life span, (2) increased iron sequestration and resultant decreases in iron availability for erythropoiesis and hemoglobin synthesis, (3) direct and indirect inhibition of erythroid pro genitor differentiation, and (4) inadequate Epo response to anemia (Fig. 1).

Fig1. MECHANISTIC UNDERPINNINGS OF ANEMIA OF CHRONIC INFLAMMATION. Circulating inflammatory cytokines cause anemia in inflammatory states through several mechanisms. (A) Decreased erythropoietin production in the kidney. (B) Direct and indirect inhibition of erythropoiesis. (C) Decreased red blood cell life expectancy in circulation and increased macrophage erythrophagocytosis. (D) Iron sequestration in cells involved in iron flows (e.g., erythrophagocytosing macrophages, hepatocytes, duodenal enterocytes) in response to increased hepcidin expression, and consequently (E) decreased iron availability for erythropoiesis. Epo, Erythropoietin; RBC, red blood cell; TF-Fe+3, transferrin-bound iron in circulation.

Cytokine-Induced Decreases in Red Blood Cell Life Span

The underlying mechanism for the reduction in RBC life span in ACI is not fully elucidated, but studies support the absence of an intrinsic RBC defect. TNF-α, IFN-γ, and IL-1 specifically enhance erythrophagocytosis by splenic macrophages, leading to a shortened RBC life span (see Fig. 1). RBCs from ACI patients have a normal life span when infused into normal subjects, suggesting an abnormality extrinsic to the RBC itself. For example, mice with elevated IFN-γ levels (either as a transgene or by exogenous administration) exhibit reduced RBC survival because of RBC removal by cytokine-stimulated macrophages. In addition, chronic sub-lethal doses of TNF-α in rats results in a 25% decline in total RBC mass and decrease in RBC survival. Furthermore, alterations in RBC rheology (deformability and aggregation) are seen in intensive care unit patients, especially those with sepsis. In vivo and in vitro experiments suggest that fever itself can induce rheologic changes in RBCs, leading to increased destruction and up to a 15% decline in RBC mass. Similarly, increased cytokines, for example IL-1, in RA patients are associated with enhanced RBC-phagocytic ability of macrophages.

Cytokines Leading to Direct and Indirect Inhibition of Erythropoiesis

Inflammatory cytokines also directly suppress erythroid precursor proliferation and differentiation (Epo responsiveness is discussed in subsequent sections). As a consequence, the bone marrow’s ability to compensate for enhanced erythrophagocytosis is hampered. Studies support a role for TNF-α, IL-1, IFN-γ, and perhaps IL-6 in this direct inhibition.

First, IFN-γ modulates gene expression involved in the in vitro proliferation of hematopoietic stem cells, thus affecting self-renewal. Second, the addition of IFN-γ to in vitro cultured erythroid progenitors increases the expression of the transcription factor PU.1. Since PU.1 directly interacts with the major erythroid transcription factor GATA-1, it is postulated that IFN-γ treatment decreases proliferation and differentiation of erythroid progenitors by a PU.1 dependent mechanism. Third, serum TNF-α levels inversely correlate with hemoglobin levels and BFU-E number in RA patients. Fourth, treatment with anti-TNF improves proliferation and decreases apoptosis of erythroid progenitor cells. The actual effect of TNF-α on erythropoiesis is likely indirect, mediated by the local release of other cytokines including IFN from accessory cells, since the inhibitory effect of TNF-α on CFU-E was completely abrogated by neutralizing antibodies against IFN-β but not by antibodies to IFN-γ or IL-1. Similarly, the effects of IL-1 also appear to be indirect since the growth of purified CFU-E is inhibited by IL-1 only in the presence of adherent T lymphocytes. This inhibition can be reversed by antibodies to IFN-γ, suggesting that IL-1 leads to lymphocyte secretion of IFN. Lastly, more recent data suggest that IL-6 may have a suppressive effect directly on erythroid precursors.

In in vitro erythroid colony formation assays derived from bone marrows of patients with ACI have shed some light specifically on extrinsic effects on erythroblast suppression. The removal of bone marrow–adherent cells (mostly macrophages and monocytes) leads to increased erythroid colony formation. This effect is lost after co culture with ACI-adherent cells but unaffected by co-culture with control bone marrow–derived adherent cells. Patients with RA have decreased BFU-E that are inversely proportional to circulating TNF levels. In parallel, culture with serum from patients with RA and anemia inhibits BFU-E proliferation, while serum from non-anemic RA patients does not. While these are not definitive studies and do not specifically delineate the factors involved, they point to an extrinsic effect on erythropoiesis.

Together, these data provide evidence of the complex crosstalk between inflammation and erythropoiesis with significant work yet to be done to enhance clarity and provide a more comprehensive understanding of the underlying molecular mechanisms beyond the mostly correlative evidence thus far.

Cytokines Leading to Decreased Erythropoietin Secretion

 Inflammatory cytokines may also influence Epo production. Epo is the essential hormone that induces erythropoiesis and elevated serum Epo is a typical finding in all anemias. The exception to this rule is the anemia in renal insufficiency which is in large part the consequence of decreased Epo production as the underlying cause of anemia. The idea of whether Epo response is or is not appropriate relative to the degree of anemia is currently only measurable in relative clinical terms. In other words, serum Epo levels compared across different diseases with similar degrees of anemia (i.e., hemoglobin level) provide relative evidence of Epo responsiveness (e.g., high Epo with low hemoglobin) or insufficient Epo levels (e.g., low Epo with low hemoglobin) (Fig. 2). In a study of 81 patients with solid tumors and clinical ACI but without tumor infiltrating the bone marrow, Epo levels were higher than in controls without anemia but half that of control subjects with IDA. Similarly, serum Epo levels are inappropriately low in HIV-positive patients with anemia and in lung transplant recipients.

Fig2. MECHANISMS UNDERLYING ERYTHROPOIETIN RESPONSIVENESS. Several mechanisms are responsible for anemia during inflammation. Inflammatory cytokine-mediated insufficient erythropoietin (Epo) production (A), anti-Epo antibodies (B), and decreased Epo responsive ness (C) are implicated. While decreased Epo production and anti-Epo anti bodies lead to insufficient Epo stimulation of erythropoiesis, decreased Epo responsiveness correlates with higher than normal Epo levels, despite which a proportional increase in hemoglobin is not observed. Decreased Epo responsiveness may be a consequence of both direct cytokine-mediated suppression of erythroid differentiation despite increased Epo and iron restriction in high hepcidin conditions, e.g., anemia of chronic inflammation. In the iron-replete condition, small amounts of Epo induce proliferation and differentiation of erythroblasts that take up circulating transferrin-bound iron, enabling hemoglobin synthesis. During iron deficiency, circulating transferrin-bound iron is decreased, resulting in decreased hemoglobin synthesis per cell and decreased Epo responsiveness, modifying Epo receptor-dependent signaling to support cell viability in excess of erythroid proliferation and differentiation.

To understand how inflammation may cause decreased serum Epo, several hypotheses can be explored. First, both cytokine-mediated alterations in binding affinities of Epo-inducing transcription factors and damage of Epo-producing cells have been hypothesized as potential mechanisms. For example, lipopolysaccharide (LPS) injection to induce inflammation in mice results in decreased Epo mRNA expression in the kidney and decreased serum Epo levels. Second, IL-1α, IL-1β, and TNF-α significantly decrease Epo production in kidney cell cultures, and IL-1β inhibits Epo production in perfused rat kidneys. Third, autoantibodies to Epo have been detected in sub jects with autoimmune diseases (e.g., systemic lupus erythematosus [SLE]) and may contribute to low circulating Epo levels even in the absence of renal involvement in these diseases. Fourth, Epo may not function optimally in the presence of inflammatory cytokines. Epo resistant subjects with end-stage renal disease (ESRD) are more likely to have elevated inflammatory cytokines, and peripheral blood mono nuclear cells isolated from Epo-refractory ESRD subjects are more likely to produce inflammatory cytokines than are those from non Epo-refractory ESRD subjects.

The fact that exogenous Epo can often at least partially reverse ACI suggests strongly that insufficient Epo production is one of the underlying causes of ACI. In parallel, low-dose Epo administration in rats leads to more normal endothelial function, reverses vascular inflammation, and decreases oxidative stress, suggesting that Epo or its downstream effects may also decrease inflammation. Increasing Epo also indirectly decreases hepcidin via the induction of a recently recognized Epo-dependent erythroid suppressor of hepcidin, erythroferrone (ERFE), leading to reversal of iron sequestration and increasing iron availability for erythropoiesis to improve anemia.

Cytokine-Induced Changes in Iron Metabolism

 There is now a consensus view that ACI is in large part a consequence of altered iron metabolism. Specifically, production of inflammatory cytokines, such as IL-6, and possibly other cytokines leads to hepcidin-induced hypoferremia, resulting in iron sequestration within the reticuloendothelial system, thereby decreasing iron availability for erythropoiesis (Figs. 1 and 2). IL-6 induction of hepcidin expression is mediated through STAT3 signaling in hepatocytes (Fig. 3). Crosstalk between IL-6–induced STAT3 signaling and BMP/SMAD signaling to hepcidin provides the rationale for manipulating the BMP/SMAD pathway also in ACI. For example, the SMAD binding site on the hepcidin promoter remains essential for IL-6–mediated hepcidin expression and liver-specific Smad4 knock out mice demonstrate diminished hepcidin responsiveness to IL-6. In vitro experiments reveal that blocking BMP receptor signaling inhibits IL-6-mediated hepcidin expression.

Fig3. MULTIFACTORIAL REGULATION OF HEPCIDIN EXPRESSION IN HEPATOCYTES. Hepcidin is regulated via multiple pathways. In inflammatory states, macrophages release IL-6 which activates the STAT3 pathway in hepatocytes, leading to production of hepcidin. Local iron stores induce non-hepatocyte liver cells to produce BMPs (i.e., BMP2 and BMP6) that stimulate BMP receptor I, activating the SMAD1/5/8 path way which, in concert with SMAD4, translocate to the nucleus to induce hepcidin transcription. ALK, Activin A receptor-like kinase; BMP, bone morphogenetic protein; BMPR, BMP receptor; HAMP, gene encoding hepcidin; IL-6, interleukin 6; LSEC, liver sinusoidal endothelial cell; SMAD, s-mothers against decapentaplegic; STAT3, signal transducer and activator 3.

In support of the role of IL-6 and hepcidin in ACI, mice injected with IL-6 exhibit increased hepcidin levels and develop hypoferremia within 24 hours. LPS injection (which leads to IL-6 induction) did not induce hypoferremia in IL-6 knockout mice. In humans, LPS injection dramatically increases IL-6 levels in 3 hours and increased urinary hepcidin in 6 hours. Finally, loss of both IL-6 and hepcidin in mouse models results in a milder anemia and more rapid recovery of hemoglobin in a well-established mouse model of ACI, and IL-6 knockout animals exhibited faster bone marrow recovery relative to hepcidin knockout animals. Other pro-inflammatory cytokines, such as TNF and IL-1, also lead to increased iron content in macro phages (see Fig. 1). Rats injected with IL-1 or TNF experienced a 40% drop in serum iron levels, leading to a significant decrease in erythroblast iron uptake. Finally, in vitro studies demonstrate that the addition of TNF increases radiolabeled iron uptake by peritoneal macrophages without an increase in iron release, suggesting that macrophage sequestration of iron is cytokine-induced.

The peptide hormone hepcidin is the principal regulator of iron homeostasis, including dietary iron absorption, iron recycling by macrophages, and the release of iron from hepatic stores (see Fig. 1). Hepcidin down regulates iron release into plasma by binding to and functionally down regulating ferroportin 1 (FPN1), the sole iron exporter in enterocytes. When FPN1 is lost in the duodenum, absorption of dietary iron is reduced and serum iron levels are depressed; similarly, hepcidin inhibits FPN1 and iron export from macrophages, aggravating the low serum iron levels and enhancing iron retention in the macrophage. Iron retention within monocytes/macrophages induces ferritin expression and accounts for the increase in serum ferritin concentration in inflammatory states. The net result is serum hypoferremia and hyperferritinemia.

Hepcidin-independent mechanisms also contribute to altered iron homeostasis and are mainly orchestrated by cytokines (as well as hypoxia). TNF-α, IL-1, IL-6, and IFN-γ all increase macrophage iron uptake by altering the expression of TfR1 and diva lent metal transporter-1 (DMT1). In addition, many of these cytokines, including IL-4, IL-10, and IL-13, contribute to increased iron storage within the monocytes/macrophages by increasing the expression of ferritin both transcriptionally and post-transcriptionally. Transcription of FPN1 is also inhibited by IFN-γ and LPS, thereby contributing to iron sequestration in macrophages.

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