(233f) Intrinsic and Extrinsic Regulation of Macrophage Polarization in Immunological Microenvironments

Immunological microenvironments play central roles in nearly every chronic disease, including cancer, infections, and autoimmune disease. Surprisingly, we know little about how the cellular networks within these environments operate. An important feature of these networks is that immune cells such as macrophages and dendritic cells can adopt alternative functional states (e.g., either pro- or anti-inflammatory), which is known as ?polarization?, and can interconvert between these states, a capability termed functional ?plasticity?. Tumors and pathogens manipulate this balance to force the local immune network into an impaired state, preventing immune clearance and posing a major barrier to therapeutic intervention. Here, we investigate the mechanisms by which macrophages regulate the polarization choice, a process that remains poorly understood. The canonical view is that external cues guide polarization in an essentially deterministic fashion. However, new evidence suggests that individual macrophages respond stochastically to identical stimuli. We have also observed that delivering ?incoherent? stimuli (e.g., a mixture of molecules that each individually drives polarization towards a distinct state) induces a transient diversity of cellular states that becomes less pronounced over time. We hypothesize that polarization dynamics are regulated by a balance between intrinsic mechanisms (which may generate an initial diversity of functional states) and extrinsic mechanisms (which allow neighboring cells to collectively ?vote? for one functional state or another, for example by secreting auto-regulatory cytokines to a common local pool). Such coordination between responding immune cells could provide a mechanism for managing and regulating functional variability. We have developed a system for tracking polarization in individual cells within a population in real time and experimentally manipulating interactions within these cellular networks. Here we will present data that provide new insights into this medically important phenomenon.