Researchers report a mechanism by which inflammation contributes to development of anemia in the November issue of Gastroenterology. The process involves increased liver expression of a microRNA that reduces production of erythropoietin in kidney. Strategies to block this miRNA might help prevent anemia in patients with chronic inflammation.
Anemia is associated with acute and chronic inflammation, but little is known about mechanisms of this interaction. Lipopolysaccharide (LPS) is a large molecule comprising a lipid and a polysaccharide that is a membrane component of gram-negative bacteria found in the intestine. When the lining of the intestine becomes leaky, LPS can enter the bloodstream, cause inflammation, and move to the liver.
Mila Rivkin et al looked for factors produced by liver in response to LPS and inflammation that might alter levels of erythropoietin. They found that expression and secretion of the microRNA-122 (MIR122) increased in liver cells exposed to the inflammatory cytokine tumor necrosis factor (TNF), via activation of the transcription factor NF-κB.
MIR122 is highly expressed in liver and secreted into the bloodstream. This small non-coding RNA has been shown to regulate cholesterol and fatty-acid metabolism, and has been associated with viral-, alcohol-, and chemical-induced liver injury.
Rivkin et al found that injection of mice with LPS led to increased plasma levels of MIR122, but levels in liver decreased to basal levels, indicating a move of MIR122 from liver to the blood. This change required TNF. The authors also found levels of MIR122 to increase in mouse kidney after LPS injection, but not in the other tissues they tested.
Finding that LPS causes an increase in plasma MIR122 led the authors to search for target genes. A bioinformatic search predicted EPO mRNA, which encodes erythropoietin, to be a target. The authors confirmed that expression of MIR122 in a human kidney cell line reduced levels of EPO mRNA.
What happens in vivo? Rivkin et al injected MIR122 into mice that had been given earlier injections of phenylhydrazine. Phenylhydrazine causes lysis of red blood cells, resulting in hemolytic anemia and increased production of erythropoietin in mice. However, in mice given injections of MIR122, plasma levels of EPO were reduced significantly.
Injection of mice with an oligonucleotide antagonist of MIR122 increased blood levels of erythropoietin, reticulocytes, and hemoglobin.
The authors found an inverse relationship between blood levels of MIR122 and erythorpoietin in mice with acute pancreatitis or steatohepatitis, and also in patients with acute inflammation.
Rivkin et al conclude that miR122 is a nucleic acid that acts like a hormone, linking the gut, liver, and kidney in controlling levels of erythropoietin. LPS-induced inflammation increases blood levels of MIR122, which reduces expression of EPO in the kidney, resulting in inflammation-induced anemia (see figure).
Recombinant erythropoietin (rhEPO) is used to treat anemia in patients with chronic kidney disease and cancer. However, rhEPO could accelerate tumor growth or promote cardiovascular events. Erythropoietin and its receptor are expressed in many tumors, including liver cancer. The authors state that the risks associated with rhEPO treatment should be an incentive for developing alternative therapies.
Strategies to block MIR122 in patients with inflammation could reduce the development or progression of anemia without the risks of rhEPO.