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

The inflammatory and anti-inflammatory M phi s have been implicated in many diseases including rheumatoid arthritis, multiple sclerosis, and leprosy. Recent studies suggest targeting M phi 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 M phi subsets. We have shown previously that human monocytes are highly susceptible whereas differentiated M phi s (M0) are highly resistant to the cytocidal abilities of SMs. To determine whether human M phi subsets are resistant to the cytotoxic effects of SMs, we show that M1 M phi s 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 M phi s was mediated by apoptosis as well as necroptosis, activated both extrinsic and intrinsic pathways of apoptosis, and was attributed to the IFN-gamma-mediated differentiation. In contrast, M2c and M0 M phi s experienced cell death through necroptosis following simultaneous blockage of the IAPs and the caspase pathways. Overall, the results suggest that survival of human M phi s 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.

Automated summary

The study shows that human macrophage subsets respond differently to cell death mechanisms and exhibit varying resistances to certain drugs, suggesting potential for targeted therapies in various inflammatory diseases.