Anemia of inflammation and the key role of autophagy: one step closer to identifying therapeutic targets?

One of the lesser known – but extremely common – complications of cancer that causes ‘anemia’ is a chronic inflammation. Anemia of inflammation not only causes fatigue and reduces quality of life, but has also been associated with a lower tumor responsiveness to radiotherapy. Overall, it’s a bad prognostic factor for survival. So, finding ways to alleviate anemia of inflammation is a priority – but to do so, researchers need to understand how anemia of inflammation comes about in the first place, and on a molecular level.

The path to disease: signaling pathways

Signaling pathways involve molecules that act upon each other in turn to carry out various cell functions, a little like a relay race. Abnormal activation can lead to abnormal cell function, and so understanding exactly how these pathways work is important for identifying therapeutic targets to halt the abnormal signaling (or, trip up one of the relay runners). This is a priority for Professor Marc Diederich, Dr Franck Morceau and Dr Marion Orsini. In a recent paper, published in November 2018, they pinpoint the roles of a novel pathway that could underlie the disrupted red blood cell production seen in anemia of inflammation.

A novel pathway: the relay runners (molecules) involved

We already know that a key signaling protein involved in inflammation is tumor necrosis factor-α (TNFα), and that an increase in TNFα levels inhibits the formation of red blood cells. TNFα is also known to activate a signaling pathway called the ‘sphingomyelinase/ceramide pathway’. Activation of this pathway has several consequences, including the production of the lipid molecule, ceramide. While ceramide has been reported to be involved in the inhibition of red blood cell production, its specific role in TNFα-mediated impairment of red blood cell production was investigated for the first time in this recent paper.

Autophagy: an involvement in impaired red blood cell production?

TNFα-induced activation of the sphingomyelinase/ceramide pathway also results in the regulation of ‘autophagy’ (which comes from the Greek “auto” and “phagein”, meaning self-eating), the process by which cells degrade and recycle their components. Autophagy is essential for red blood cell production and the loss of autophagy can result in severe anemia. In a recent review, Diederich and colleagues highlighted the potential for using autophagy modulators to treat various blood disorders, including cancers. Targeting autophagy and its mediators could therefore have real clinical significance in terms of drug development.

The finish line: red blood cell production

In this most recent study, published in Cell Death & Differentiation, Morceau and Orsini found that the TNFα/sphingomyelinase/ceramide pathway inhibits red blood cell development and switches this process to that of the production of granulocytes, which are a major component of the innate immune system – ceramides seemed to play a key role in this. They also found that this pathway inhibits autophagy, and this occurs via activation of a protein called mTOR. mTOR is an essential regulator of many cell functions and was previously identified as an interesting target for blood disorders by Diederich’s lab. Most importantly, these new findings highlight the essential role of autophagy in the impairment of red blood cell production.