Selective Induction of Cell Death by Smac Mimetics in Primary Human Proinflammatory and Anti-inflammatory Macrophage Subsets

FieldValue
dc.contributor.authorAli, Hamza
dc.date.accessioned2021-02-23T20:09:45Z
dc.date.issued2021-02-23
dc.identifier.urihttp://hdl.handle.net/10393/41822
dc.identifier.urihttp://dx.doi.org/10.20381/ruor-26044
dc.description.abstractThe inflammatory and anti-inflammatory macrophages have been implicated in many diseases including rheumatoid arthritis, inflammatory bowel disease and chronic rhinosinusitis. Recent studies suggest targeting macrophage function and activation may represent a potential target to treat these diseases. Herein, I investigated the effect of second mitochondria-derived activator of caspases (SMAC) mimetics (SMs), the inhibitors of apoptosis (IAPs) proteins, on the killing of normal human pro- and anti-inflammatory macrophage subsets. It has been shown that human monocytes are highly susceptible to the cytotoxic effects of SMs, however, differentiated macrophages (M0) develop resistance to the cytocidal abilities of SMs. Whether human macrophage subsets are also resistant to the cytotoxic effects of SM remains unknown. My results show that differentiation of M0 macrophages towards M1 state rendered them highly susceptible to SM-induced cell death, whereas M2a, M2b and M2c differentiated subsets were resistant, with M2c being the most resistant. SM-induced cell death in M1 macrophages was mediated by apoptosis as well as necroptosis and activated both extrinsic and intrinsic pathways of apoptosis. The susceptibility of M1 macrophages to SM-induced cell death was attributed to the IFN-𝛾-mediated polarization as JAK inhibitor reversed their susceptibility. In contrast, M2c and M0 macrophages experienced cell death through necroptosis pathway following simultaneous blockage of the IAPs pathways by SM-LCL161 and the caspase pathways by the pan-caspase inhibitors (zVAD.fmk). I investigated the molecular mechanism governing SM-induced cell death in M1 macrophages. My results show that in contrast to the cancer cell lines, SM-induced cell death in M1 macrophages is independent of endogenously produced TNF-⍺, the canonical and non- canonical NF-𝜅B pathways. The susceptibility of M1 macrophages to SM-induced cell death was found to be dependent on IFN-𝛾-mediated differentiation through the JAK-STAT pathway and subsequent activation of IRF-1. In addition, the selective cell death in SM-treated M1 macrophages is mediated by simultaneous degradation of cellular IAP-2 (cIAP-2) and RIPK-1/3 through the activation of mTORC signaling pathway. Overall, the results suggest that survival of human macrophages is critically linked to the activation of the IAPs pathways. Moreover, agents blocking cIAP-1/2, mTORC and IRF-1 can be exploited therapeutically to address inflammation-related diseases. These observations hold a promising therapeutic strategy to limit the activation of proinflammatory M1 macrophages and eventually controlling the M1-associated diseases.
dc.language.isoen
dc.publisherUniversité d'Ottawa / University of Ottawa
dc.subjectHuman macrophages subsets
dc.subjectSMAC mimetics (SMs)
dc.subjectInhibitors of apoptosis (IAPs)
dc.subjectApoptosis
dc.subjectNecroptosis
dc.subjectmTORC
dc.subjectIFR-1
dc.titleSelective Induction of Cell Death by Smac Mimetics in Primary Human Proinflammatory and Anti-inflammatory Macrophage Subsets
dc.typeThesis
dc.contributor.supervisorKumar, Ashok
dc.embargo.terms2022-02-23
dc.embargo.lift2022-02-23
thesis.degree.namePhD
thesis.degree.levelDoctoral
thesis.degree.disciplineMédecine / Medicine
uottawa.departmentBiochimie, microbiologie et immunologie / Biochemistry, Microbiology and Immunology
CollectionThèses - Embargo // Theses - Embargo

Files