But not males13. Rather, as demonstrated here, the dominant impact of GMCSF in Ldlr-/- mice is enhancement of macrophage apoptosis in sophisticated atherosclerosis by a certain mechanism related to its capability to induce IL-23 production. The outcomes in the present study Caspase 1 medchemexpress underscore the value in the cytokine-inducing function of GM-CSF in atherosclerosis, which in this case includes a specific CA I list cytokine, IL-23, that promotes macrophage apoptosis. Beneath physiologic conditions, GM-CSF-induced production of IL-23 and subsequent macrophage apoptosis could act as a feedback mechanism to control immune cell populations or to prevent excessive inflammation. In that setting, the apoptotic macrophages would be rapidly cleared by neighboring phagocytes (efferocytosis), which prevents each secondary necrosis and generation of pro-inflammatory damage-associated molecular patterns (DAMPS) and also activates anti-inflammatoryCirc Res. Author manuscript; obtainable in PMC 2016 January 16.Subramanian et al.Pagesignaling pathways in the efferocytes themselves49. On the other hand, in sophisticated atherosclerotic lesions, efferocytosis is defective50, and so processes that increase apoptosis promote necrosis and inflammation, which, as demonstrated right here, is the case with GM-CSF-induced IL-23. The hyperlink in between GM-CSF and IL-23 has been explored most extensively in the setting of autoimmune problems, exactly where a GM-CSF/IL-23/Th17 axis has been demonstrated to play a significant role in disease exacerbation3, 24. Accordingly, anti-GM-CSF, anti-IL-23, and antiIL-17 therapies are presently beneath investigation for treatment of these diseases12, 51. In these issues, mechanistic studies have focused on the part of IL-23 in advertising Th17 cell survival and Th17-mediated IL-17 production. In sophisticated atherosclerosis, on the other hand, the pathogenic impact of IL-23 seems to become largely independent of IL-17 generation, as neutralization of IL-17 activity did not block IL-23-induced macrophage apoptosis or plaque necrosis. In addition, IL-23, but not IL-17, increased apoptosis in 7KC-treated macrophages. IL-23 has been shown previously to induce apoptosis in self-reactive thymocytes27, and, at high concentration, in B-acute lymphoblastic leukemia cells (B-ALL)28. In B-ALL cells, like macrophages, the pro-apoptotic mechanism of IL-23 entails down-regulation of Bcl-2. In B-ALL cells, even so, Bcl-2 down-regulation is mediated by a microRNA, miR15a28, when in macrophages, Bcl-2 down-regulation is mediated by the proteasome following MKP-1-mediated Bcl-2 dephosphorylation. Our lab has previously shown that atherosclerosis-prone mice lacking macrophage-Bcl-2 have enhanced lesional macrophage apoptosis and improved necrotic area52, which demonstrates that Bcl-2 is critical for macrophage survival in advanced atherosclerosis. The current study delivers a pathophysiolgically relevant context for this impact, namely, GMCSF/IL-23-mediated down-regulation of macrophage Bcl-2. The classic function of Bcl-2 is suppression of the mitochondrial-caspase-9 pathway of apoptosis37, but our information too as preceding studies41, 42 suggest that Bcl-2 may also suppress intracellular oxidant pressure. Offered the role of ROS in macrophage apoptosis18, we propose the GM-CSF/IL-23 pathway, by way of destabilizing Bcl-2, promotes apoptosis susceptibility in macrophages by increasing both caspase-9 activity and intracellular ROS. The precise mechanism by means of which Bcl-2 regulates intracellular ROS in other models isn’t effectively understood,.
