Selective killing of human M1 macrophages by Smac mimetics alone and M2 macrophages by Smac mimetics and caspase inhibition

Abstract

The inflammatory and anti‐inflammatory Mϕs have been implicated in many diseases including rheumatoid arthritis, multiple sclerosis, and leprosy. Recent studies suggest targeting Mϕ function and activation may represent a potential target to treat these diseases. Herein, we investigated the effect of second mitochondria‐derived activator of caspases (SMAC) mimetics (SMs), the inhibitors of apoptosis (IAPs) proteins, on the killing of human pro‐ and anti‐inflammatory Mϕ subsets. We have shown previously that human monocytes are highly susceptible whereas differentiated Mϕs (M0) are highly resistant to the cytocidal abilities of SMs. To determine whether human Mϕ subsets are resistant to the cytotoxic effects of SMs, we show that M1 Mϕs are highly susceptible to SM‐induced cell death whereas M2a, M2b, and M2c differentiated subsets are resistant, with M2c being the most resistant. SM‐induced cell death in M1 Mϕs was mediated by apoptosis as well as necroptosis, activated both extrinsic and intrinsic pathways of apoptosis, and was attributed to the IFN‐γ‐mediated differentiation. In contrast, M2c and M0 Mϕs experienced cell death through necroptosis following simultaneous blockage of the IAPs and the caspase pathways. Overall, the results suggest that survival of human Mϕs is critically linked to the activation of the IAPs pathways. Moreover, agents blocking the cellular IAP1/2 and/or caspases can be exploited therapeutically to address inflammation‐related diseases.

Role of RIPK1 in SMAC mimetics-induced apoptosis in primary human HIV-infected macrophages

“…HIV infection results in dysregulation of cytokine profile in-vivo and in-vitro 62 and can possibly affect the polarization state of macrophages . Since IFN-γ-generated M1 macrophages are susceptible to SM-mediated cell death 49 , HIV-1 infection may polarize macrophages into M1 phenotype and make them susceptible to SM-induced apoptosis. Since in vitro-infected and ex vivo - derived macrophages exposed to SM were not polarized into M1 phenotype suggested that SM-mediated killing of HIV-infected macrophages was not due to M1 polarization.…”

Non-apoptotic activity of the mitochondrial protein SMAC/Diablo in lung cancer: Novel target to disrupt survival, inflammation, and immunosuppression

“…Moreover, the infiltration of effector T cells within tumors treated with tSMAC show low expression of PD-1 ( 12 ). It was also shown that SMAC mimetics, which competitively inhibit SMAC-cIAP-1/2 interaction and thus repress anti-apoptotic functions of IAP proteins, elicit proinflammatory cell death in cancer cells that engages an adaptive antitumor immune response ( 104 ). These finding support our results proposing an additional function for SMAC related to anti-tumor immunity.…”

Apoptosis, Autophagy, NETosis, Necroptosis, and Pyroptosis Mediated Programmed Cell Death as Targets for Innovative Therapy in Rheumatoid Arthritis

“…Studies have shown that second mitochondriaderived activator of caspases (SMAC) mimetics (SMs) can inhibit the anti-apoptotic effect of Smac, which is a member of the IAP family protein, by competing with CIAP1/2 protein to induce the activation of caspase-3, caspase-7, caspase-8, caspase-9, and Fas; thereby facilitating the release of TNF-a; and in vitro activation of RIPK1, RIPK3, and MLKL in pro-inflammatory M1 macrophages to activate apoptosis and necroptosis. Blockade of the IAP and caspase pathways, facilitates M2c phenotype induction by SMs, resulting in necroptosis of M0 macrophages (177). Compared with etanercept, a TNF-a inhibitor, geldanamycin inhibits the RIPK1 and NF-KB activity while augmenting the activation of caspase-8 to promote MH7A cell apoptosis, and inhibit TNF-a-induced necroptosis.…”