Inhibitors of Apoptosis Protein Antagonists (Smac Mimetic Compounds) Control Polarization of Macrophages during Microbial Challenge and Sterile Inflammatory Responses

Abstract

Apoptosis is a physiological cell death process essential for development, tissue homeostasis, and for immune defense of multicellular animals. Inhibitors of apoptosis proteins (IAPs) regulate apoptosis in response to various cellular assaults. Using both genetic and pharmacological approaches we demonstrate here that the IAPs not only support opportunistic survival of intracellular human pathogens like Chlamydia pneumoniae but also control plasticity of iNOS+ M1 macrophage during the course of infection and render them refractory for immune stimulation. Treatment of Th1 primed macrophages with birinapant (IAP-specific antagonist) inhibited NO generation and relevant proteins involved in innate immune signaling. Accordingly, birinapant promoted hypoxia, angiogenesis, and tumor-induced M2 polarization of iNOS+ M1 macrophages. Interestingly, birinapant-driven changes in immune signaling were accompanied with changes in the expression of various proteins involved in the metabolism, and thus revealing the new role of IAPs in immune metabolic reprogramming in committed macrophages. Taken together, our study reveals the significance of IAP targeting approaches (Smac mimetic compounds) for the management of infectious and inflammatory diseases relying on macrophage plasticity.

Tempering Macrophage Plasticity for Controlling SARS-CoV-2 Infection for Managing COVID-19 Disease

“…Apart from these, we have validated several other immune adjuvants, such as low dose Gamma Radiation (Klug et al, 2013;Prakash et al, 2016), S-1P (Nadella et al, 2019), and Smac mimetics (Nadella et al, 2017), which indicate the potential of the Th1 programming of macrophages in a pre-clinical model system. These adjuvants are likely to create immunity against SARS-CoV-2 infection in the animal models discussed above.…”

Dysbiosis Disrupts Gut Immune Homeostasis and Promotes Gastric Diseases

“…We [52] and others [53,54,55] have previously demonstrated that many pathogenic microbes which are associated with cancer reprogram macrophages immunologically and metabolically during persistency. Apart from this, many pathogenic bacteria/viruses like Helicobacter pylori , Fusobacterium nucleatum , and Chlamydia sp.…”

The Immune Mechanisms of Lung Parenchymal Damage in Tuberculosis and the Role of Host-Directed Therapy

“…In in vitro models, metformin, a widely used antidiabetic agent, has been shown to inhibit TNF production by monocytes ( Arai et al, 2010 ), affect macrophage polarization ( Nadella et al, 2017 ), and promote autophagy ( Singhal et al, 2014 ). It affects Th1 responses, but data are conflicting: in mice infected with TB, metformin treatment promotes the expansion of Mtb -specific IFN-γ secreting T cells in the lungs ( Singhal et al, 2014 ), whereas in human THP-1 cells (not infected with Mtb ) metformin suppressed the production of Th1-related cytokines ( Chen et al, 2018 ).…”