It's Getting Hot In Here: CD163 and Inflammation

Hemoglobin is an intracellular protein that carries oxygen throughout the body and has toxic effects when outside the cell, because it reacts with molecules like carbon monoxide, nitrogen monoxide, and peroxide. One of the toxic effects of hemoglobin is inflammation².

Malaria is not the only disease that results in toxic, extracellular hemoglobin. A genetic disease has a similar effect: sickle cell disease. Sickle cell disease is a condition in which red blood cells are distorted into a sickle shape. Because of their shape, the cells degrade prematurely, resulting in chronic, low levels of extracellular hemoglobin, causing inflammation³.

Hemoglobin can also cause localized inflammation and toxicity. Atherosclerosis is a disease caused by plaques deposited on the inner walls of arteries. Plaque build-up narrows the arteries, restricting blood flow. As plaque build-up advances, micro bleeding occurs, leading to an accumulation of cholesterol, hemoglobin and other red blood cell components. The accumulation of hemoglobin at the plaque build-up site is a hotspot for inflammation⁴.

Besides disease, treatments that are meant to be therapeutic can also result in extracellular hemoglobin. Hemoglobin-based oxygen carriers (HBOCs) are fluids intended to replace low levels of blood cells in patients such as those with sickle cell disease. Because of the high concentration of hemoglobin in HBOCs, there is also a higher concentration of shed, extracellular hemoglobin than can be managed by the body⁵. Blood transfusions can also contain degraded, extracellular hemoglobin, stimulating toxic effects and inflammation seen in the above diseases⁶.

Luckily, the body has mechanisms in place to respond to extracellular hemoglobin. Scavenger receptors bind and remove pathogen-associated molecular patterns (PAMPs). A major scavenger receptor for hemoglobin is CD163, a protein primarily expressed in white blood cells: monocytes and macrophages. Macrophages are phagocytic (cell-eating) cells which engulf and destroy their targets. With the help of CD163, they can target extracellular hemoglobin. Since CD163 targets pro-inflammatory hemoglobin, CD163 indirectly contributes to the anti-inflammatory response⁷.

In addition to targeting hemoglobin for macrophages, CD163 also serves as an inflammation marker. Macrophages that express high levels of CD163 protein indicate the presence of inflammation7. As macrophages express CD163, the protein is cleaved and shed into the blood. Levels of shed CD163 in blood plasma are increased in diseases like the ones described. Keeping track of CD163 could be a way to monitor the bodies response to extracellular hemoglobin and disease progression. CD163 could also be used as a marker for targeting hemoglobin for therapeutic intervention⁸.

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