The Multiple Facets of Iron Recycling

Abstract

The production of around 2.5 million red blood cells (RBCs) per second in erythropoiesis is one of the most intense activities in the body. It continuously consumes large amounts of iron, approximately 80% of which is recycled from aged erythrocytes. Therefore, similar to the “making”, the “breaking” of red blood cells is also very rapid and represents one of the key processes in mammalian physiology. Under steady-state conditions, this important task is accomplished by specialized macrophages, mostly liver Kupffer cells (KCs) and splenic red pulp macrophages (RPMs). It relies to a large extent on the engulfment of red blood cells via so-called erythrophagocytosis. Surprisingly, we still understand little about the mechanistic details of the removal and processing of red blood cells by these specialized macrophages. We have only started to uncover the signaling pathways that imprint their identity, control their functions and enable their plasticity. Recent findings also identify other myeloid cell types capable of red blood cell removal and establish reciprocal cross-talk between the intensity of erythrophagocytosis and other cellular activities. Here, we aimed to review the multiple and emerging facets of iron recycling to illustrate how this exciting field of study is currently expanding.

Impaired iron recycling from erythrocytes is an early hallmark of aging

“…Since the unique architecture of the spleen confers a filter for verifying the biomechanical integrity of RBCs (Mebius and Kraal, 2005; Slusarczyk and Mleczko-Sanecka, 2021), we observed only local but not systemic dyshomeostasis of RBCs during aging. Most importantly, we found that splenic RBCs of aged mice show ROS accumulation, a characteristic feature of senescent RBCs, and a risk factor for enhanced hemolysis (Zhang et al, 2018).…”

“…2A). However, defective RBCs are first filtered in the spleen due to the loss of their elasticity, and this step is a prerequisite for their removal via EP (Slusarczyk and Mleczko-Sanecka, 2021). In agreement with this model, RBCs that are retained in the spleen of young mice show ROS build-up, a marker of their senescence (Bratosin et al, 1998), compared to the circulating RBCs (Fig.…”

“…RPMs play an essential role in preventing the release of hemoglobin from RBCs and maintaining the internal recycling of the body iron pool (Slusarczyk and Mleczko-Sanecka, 2021). To date, impairments of their functions have been reported in genetically modified mice, including models with an almost complete or partial loss of RPMs due to the absence of genes that control RPMs differentiation, such as Pparg, Spi-c, Il-33 , or its receptor Il1rl1 (Kohyama et al, 2009; Lu et al, 2020; Okreglicka et al, 2021).…”

“…Once RBCs become too rigid to pass through slits within the red pulp’s unique venous system, they are retained within the spleen cords (Mebius and Kraal, 2005). Recognition of ‘trapped’ RBCs by RPMs involves additional signals proposed to act in an additive fashion (Gottlieb et al, 2012; Slusarczyk and Mleczko-Sanecka, 2021). Upon engulfment by RPMs, RBCs are degraded in phagolysosomes, globins are hydrolyzed to amino acids, and heme is released (Klei et al, 2017).…”

“…Sufficient iron supplies are critical for metabolic cellular functions and red blood cells (RBCs) production (Cronin et al, 2019; Muckenthaler et al, 2017). As a key constituent of heme - a prosthetic group of hemoglobin, iron confers the unique capability of RBCs to shuffle oxygen and carbon dioxide between the lungs and tissues (Slusarczyk and Mleczko-Sanecka, 2021). At the systemic level, 80% of circulating iron is utilized for hemoglobin synthesis during the daily generation of approximately 200 billion RBCs (Muckenthaler et al, 2017).…”