MARTINA MUCKENTHALER (HEIDELBERG)
MACROPHAGE AND IRON
Macrophages not only play a central role in the recycling of iron from damaged red blood cells
but represent immune cells that determine our responses to infectious and inflammatory
stimuli (1). We recently explored links between these two functions in hemolytic diseases,
including sickle cell anemia and thalassemia. The enhanced release of hemoglobin and heme
into the circulation in sickle cell disease causes heme-iron loading of macrophages, and
chronic inflammation. We showed that exposure to heme/iron induces a proinflammatory
phenotype in cultured macrophages, hallmarked by elevated expression of inflammatory
cytokines. The heme/ iron-induced sterile inflammation in macrophages contributed to liver
fibrosis in a disease model for sickle cell disease, replicating human pathology (2).
In the tumor microenvironment (TME) macrophages represent a major immune component.
These tumor-associated macrophages (TAMs) are frequently detected in an anti-inflammatory
state that promote tumor activities such as immune system suppression and
metastases formation while facilitating chemotherapeutic resistance. We recently identified
an entirely new subset of TAMs that are iron- loaded, pro-inflammatory and localized in
hemorrhagic areas of the TME. The occurrence of these iron-loaded TAMs (iTAMs) correlated
with reduced tumor size in patients with non-small cell lung cancer (3) and improved survival
of patients with lung adenocarcinoma (4). In culture iTAMs were capable of directly killing
tumor cells. Interestingly, when tested in vivo, tumors injected with a novel iron nanoparticle
targeted for macrophages led to significantly smaller tumor sizes compared to controls (3).
In my presentation I will summarize our findings that hemolysis induces sterile inflammation
in macrophages and its pathophysiological consequences in hemolytic disease and the tumor
microenvironment.
Selected literature from the lab
(1) Muckenthaler et al., Cell 2017;168(3):344
(2) Vinchi, da Silva et al., BLOOD; 2016; 127(4):473
(3) Da Silva et al., Frontiers in Immunology; 2017; 8, 1479 (4) Thielmann et al., Sci Rep; 2019; 9, 11326