Heme Oxygenase-1 Contributes to an Alternative Macrophage Activation Profile Induced by Apoptotic Cell Supernatants

Abstract

Apoptotic cells (AC) are rapidly engulfed by professional phagocytes such as macrophages to avoid secondary necrosis and thus inflammation. Recognition of AC polarizes macrophages toward an anti-inflammatory phenotype, which shows homology to an alternatively activated M2 macrophage. However, mechanistic details provoking these phenotype alterations are incompletely understood. Here, we demonstrate a biphasic up-regulation of heme oxygenase-1 (HO-1), a protein that bears an antiapoptotic as well as an anti-inflammatory potential, in primary human macrophages, which were exposed to the supernatant of AC. Although the first phase of HO-1 induction at 6 h was accomplished by AC-derived sphingosine-1-phosphate (S1P) acting via S1P receptor 1, the second wave of HO-1 induction at 24 h was attributed to autocrine signaling of vascular endothelial growth factor A (VEGFA), whose expression and release were facilitated by S1P. Whereas VEGFA release from macrophages was signal transducer and activator of transcription (STAT) 1-dependent, vascular endothelial growth factor itself triggered STAT1/STAT3 heterodimer formation, which bound to and activated the HO-1 promoter. Knockdown of HO-1 proved its relevance in facilitating enhanced expression of the antiapoptotic proteins Bcl-2 and Bcl-X L , as well as the anti-inflammatory adenosine receptor A 2A . These findings suggest that HO-1, which is induced by AC-derived S1P, is critically involved in macrophage polarization toward an M2 phenotype.

Heat Shock Protein-Mediated Protection Against Cisplatin-Induced Hair Cell Death

“…Furthermore, protection conferred from the HO-1/macrophage axis has been demonstrated in other systems, particularly in response to ischemiareperfusion injury in the liver (Devey et al 2009). In that system, HO-1 appears to regulate the cytokine secretion profile of the macrophages in a manner in which increased HO-1 expression results in a switch from pro-to anti-inflammatory cytokine secretion (Weis et al 2009;Wegiel et al 2013). Thus, HO-1 levels may influence whether resident macrophages exhibit a pro-inflammatory phenotype that promotes cell death versus a non-inflammatory phenotype that promotes cell survival.…”

The Mononuclear Phagocyte System in Homeostasis and Disease: A Role for Heme Oxygenase-1

“…HO-1 can dampen the inflammatory response indirectly (i.e., extrinsic to the MPS) by preventing tissue injury and necrotic cell death (i.e., DAMP production). However, recent evidence has shown that HO-1 expression within cells of the immune system (i.e., intrinsic to the MPS) modulates the inflammatory response directly by affecting differentiation pathways and effector functions (11,174,183). Induction of HO-1 in human peripheral blood monocytes inhibits their chemotactic activity (115).…”

The liaison between apoptotic cells and macrophages – the end programs the beginning

“…S1P not only induced COX-2, but also upregulated heme oxygenase-1 (HO-1) in a biphasic manner. Early expression of HO-1 after 6 h was transmitted by activating the S1P receptor 1, whereas a second wave of expression was attributed to autocrine signaling of vascular endothelial growth factor A (Weis et al, 2009). HO-1 catalyzes the rate limiting step in the degradation of heme to biliverdin, ferrous iron, and carbon monoxide and is known for its anti-apoptotic and anti-inflammatory properties (Otterbein et al, 2000;Deshane et al, 2005;Kim et al, 2006).…”

“…HO-1 catalyzes the rate limiting step in the degradation of heme to biliverdin, ferrous iron, and carbon monoxide and is known for its anti-apoptotic and anti-inflammatory properties (Otterbein et al, 2000;Deshane et al, 2005;Kim et al, 2006). HO-1 was causatively involved in upregulation of Bcl-2 and Bcl-X L , explaining the mechanism behind S1P-mediated protection from apoptosis (Weis et al, 2009). …”

“…HO-1 induction by ACs also accounts for expression of the adenosine receptor A 2A (Weis et al, 2009), which is known to convey immunosuppression and blocks IL-12 formation (Hasko et al, 2007). IL-12 is necessary to activate Th1 inflammatory responses, provoking maturation of naive CD4 q T cells to Th1 effector cells and causing IFN-g secretion by CD8…”