Prohibitin: A novel regulator of inflammatory cell dynamics

Abstract

Inflammation is a complex mechanism primarily driven by the immune system to eradicate pathogens/foreign substances and restore tissue homeostasis. Despite the beneficial effects that inflammation employs, signaling can often become dysregulated leading to uncontrolled systemic inflammation and irreversible host tissue damage. Therefore, regulating the cellular and physiological mechanisms of inflammation constitutes a viable avenue of research to mitigate inflammatory disease progression. Herein, we evaluated prohibitins (PHB1 and PHB2), pleiotropic homologous proteins with known anti-inflammatory and antioxidant capabilities, in the context of systemic inflammation as well as macrophage-specific inflammatory signaling. Using two in vivo models of systemic inflammation, we found that PHB1 levels were increased in serum, suggesting a potential signaling role for PHB. Moreover, recombinant PHB1 treatment mitigated systemic inflammation and tissue/organ injury and modulated the phenotype of circulating immune cells. When investigating the role of PHB specifically in monocytes/macrophages, we found that PHB not only increased populations of pro-inflammatory monocytes in vivo but also regulated vital macrophage inflammatory signaling (as shown in vitro). We determined that PHB is a scaffold protein important for macrophage lipid raft formation and subsequent receptor trafficking. PHB modulation of macrophages influenced cell surface display of lipid-raft-dependent receptors and downstream inflammatory signaling cascades. To our knowledge, these are the first data to reveal PHB’s pro-inflammatory effects in macrophages and its mechanistic operation of lipid-raft-dependent signal transduction in macrophages. In this report, we provide insight into the diverse yet complementary roles of PHB in regulating various aspects of immune-driven inflammatory processes.