Abstract
Phenotypic changes of myeloid cells are critical to the regulation of premature aging, development of cancer, and responses to infection. Heme metabolism has a fundamental role in the regulation of myeloid cell function and activity. Here, we show that deletion of heme oxygenase-1 (HO-1), an enzyme that removes heme, results in an impaired DNA damage response (DDR), reduced cell proliferation, and increased cellular senescence. We detected increased levels of p16INK4a, H2AXγ, and senescence-associated-β-galactosidase (SA-β-Gal) in cells and tissues isolated from HO-1-deficient mice. Importantly, deficiency of HO-1 in residential macrophages in chimeric mice results in elevated DNA damage and senescence upon radiation-induced injury. Mechanistically, we found that mammalian target of rapamycin (mTOR)/S6 protein signaling is critical for heme and HO-1-regulated phenotype of macrophages. Collectively, our data indicate that HO-1, by detoxifying heme, blocks p16INK4a expression in macrophages, preventing DNA damage and cellular senescence.
Highlights
Macrophages (Mφ) play a fundamental role in eliminating invading pathogens, transformed cells via phagocytosis, coordinating immune responses through cytokine expression, and producing ROS1
Lack of heme oxygenase-1 (HO-1) induces p16INK4a expression in multiple cell types and is critical for cell cycle and macrophage function Since HO-1 deficient (Hmox1−/−) mice are characterized by increased DNA damage and inflammation[23], we reasoned that these mice could exhibit abnormal changes in their tissues due to cellular senescence
Since senescence limits the number of proliferative cycles and is associated with decreased cell functions, we assessed the proliferative capacity of primary cells in the absence of HO-1 by isolating mouse fibroblasts from Hmox1−/− and Hmox1+/+ mice and following their replication at passage 4 and 6
Summary
Macrophages (Mφ) play a fundamental role in eliminating invading pathogens, transformed cells via phagocytosis, coordinating immune responses through cytokine expression, and producing ROS1. Residential Mφ maintain homeostasis by scavenging debris of apoptotic and necrotic cells[2]. When residential Mφ are exposed to apoptotic cells repeatedly, as they are in cancer patients undergoing chemo- or radiation therapy, their clearance of these senescent cells becomes impaired[3]. Residential Mφ function in immunosurveillance against senescent cells within the tissues under pathological conditions such as during organ damage[4]. Alterations in cytokine levels in the tissue microenvironment driven by injury or bacterial infection can lead to a senile (“senescent”) phenotype of Mφ. Senile Mφ are predominantly in an active, pro-secretory state, partially due to elevated NFκB signaling. Senescenceassociated secretory phenotype (SASP) is defined by production of CCL2/MCP1, TNFα, IFNγ, IL-6, growth and differentiation factors (TGFβ and HGF), and matrix remodeling enzymes
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