Ashley M. Fenn

On-demand erythrocyte disposal and iron recycling requires transient macrophages in the liver

Iron is an essential component of the erythrocyte protein hemoglobin and is crucial to oxygen transport in vertebrates. In the steady state, erythrocyte production is in equilibrium with erythrocyte removal. In various pathophysiological conditions, however, erythrocyte life span is compromised severely, which threatens the organism with anemia and iron toxicity. Here we identify an on-demand mechanism that clears erythrocytes and recycles iron. We show that monocytes that express high levels of lymphocyte antigen 6 complex, locus C1 (LY6C1, also known as Ly-6C) ingest stressed and senescent erythrocytes, accumulate in the liver via coordinated chemotactic cues, and differentiate into ferroportin 1 (FPN1, encoded by SLC40A1)-expressing macrophages that can deliver iron to hepatocytes. Monocyte-derived FPN1+Tim-4neg macrophages are transient, reside alongside embryonically derived T cell immunoglobulin and mucin domain containing 4 (Timd4, also known as Tim-4)high Kupffer cells (KCs), and depend on the growth factor Csf1 and the transcription factor Nrf2 (encoded by Nfe2l2). The spleen, likewise, recruits iron-loaded Ly-6Chigh monocytes, but these do not differentiate into iron-recycling macrophages, owing to the suppressive action of Csf2. The accumulation of a transient macrophage population in the liver also occurs in mouse models of hemolytic anemia, anemia of inflammation, and sickle cell disease. Inhibition of monocyte recruitment to the liver during stressed erythrocyte delivery leads to kidney and liver damage. These observations identify the liver as the primary organ that supports rapid erythrocyte removal and iron recycling, and uncover a mechanism by which the body adapts to fluctuations in erythrocyte integrity.

The infarcted myocardium solicits GM-CSF for the detrimental oversupply of inflammatory leukocytes

Myocardial infarction (MI) elicits massive inflammatory leukocyte recruitment to the heart. Here, we hypothesized that excessive leukocyte invasion leads to heart failure and death during acute myocardial ischemia. We found that shortly and transiently after onset of ischemia, human and mouse cardiac fibroblasts produce granulocyte/macrophage colony-stimulating factor (GM-CSF) that acts locally and distally to generate and recruit inflammatory and proteolytic cells. In the heart, fibroblast-derived GM-CSF alerts its neighboring myeloid cells to attract neutrophils and monocytes. The growth factor also reaches the bone marrow, where it stimulates a distinct myeloid-biased progenitor subset. Consequently, hearts of mice deficient in either GM-CSF or its receptor recruit fewer leukocytes and function relatively well, whereas mice producing GM-CSF can succumb from left ventricular rupture, a complication mitigated by anti–GM-CSF therapy. These results identify GM-CSF as both a key contributor to the pathogenesis of MI and a potential therapeutic target, bolstering the idea that GM-CSF is a major orchestrator of the leukocyte supply chain during inflammation.

ANGPTL4 deficiency in haematopoietic cells promotes monocyte expansion and atherosclerosis progression

Lipid accumulation in macrophages has profound effects on macrophage gene expression and contributes to the development of atherosclerosis. Here, we report that angiopoietin-like protein 4 (ANGPTL4) is the most highly upregulated gene in foamy macrophages and its absence in haematopoietic cells results in larger atherosclerotic plaques, characterized by bigger necrotic core areas and increased macrophage apoptosis. Furthermore, hyperlipidemic mice deficient in haematopoietic ANGPTL4 have higher blood leukocyte counts, which is associated with an increase in the common myeloid progenitor (CMP) population. ANGPTL4-deficient CMPs have higher lipid raft content, are more proliferative and less apoptotic compared with the wild-type (WT) CMPs. Finally, we observe that ANGPTL4 deficiency in macrophages promotes foam cell formation by enhancing CD36 expression and reducing ABCA1 localization in the cell surface. Altogether, these findings demonstrate that haematopoietic ANGPTL4 deficiency increases atherogenesis through regulating myeloid progenitor cell expansion and differentiation, foam cell formation and vascular inflammation.

Monocytosis, Hypercholesterolemia, and the Kinase That Binds Them.

Atherosclerosis is a chronic lipid-driven inflammatory disease that involves the recruitment, infiltration, differentiation, and proliferation of monocytes and monocyte-derived macrophages. In the absence of these cells, disease neither initiates nor progresses. Indeed, leukocytosis is a defining risk factor for increased cardiovascular disease in humans.1,2 Because monocytes are involved in every step of atherosclerosis disease progression,2–4 modifying anything from recruitment to proliferation could significantly affect disease severity. Any modification needs to be extremely precise, however, because the role of monocytes changes as the disease advances. Although recruitment is the underlying culprit during the initial stages,5–7 proliferation becomes consequential later.8 MAPK (mitogen-activated protein kinases), JNK (c-Jun N-terminal kinase), and NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) can have widespread effects on cell cycle and cytokine production and may therefore be promising targets in treating complex diseases. Sanz-Garcia et al9 focus on one such kinase, Map3k8, and identify how it can be targeted to alter monocyte biology and atherosclerosis.nnSee accompanying article on page 237 nnMap3k8, also known as Tpl2 or Cot, …

EDITORIAL : Combination of Two Ancient Technologies to Improve Diagnosis of Otitis Media

A mom rushes into the pediatricians office with her screaming two-year old girl, Becca. Becca has been irritable for several...