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Immune cells encounter an enormous variety of threats, from small rigid bacteria to malleable cancer cells and irregularly shaped microplastics. Beyond biochemical signals, the diverse physical properties of such targets have emerged as key regulators of immune responses. In our lab we focus on innate immune cells, which are the first responders to these threats, and which use biophysical cues to guide target selection and enhance target killing. We use a profoundly interdisciplinary approach, combining development of controlled microparticles to interrogate immune functions, with quantitative imaging, molecular biology approaches and development of new biophysical approaches. In this talk, I will present our recent work revealing that stiffer spherical particles are phagocytosed (i.e. eaten) more efficiently than softer ones. Surprisingly, and in stark contrast to spheres, uptake of microrods is more efficient for softer than stiffer rods. Rigidity dependence of rod uptake persists up to unusually high stiffness (~1 MPa) and is integrin-independent. Instead, the overall bending flexibility of rods seems to regulate phagocytosis. Live-cell imaging experiments reveal minimal bending of soft microrods during phagocytic engulfment, and suggest that rigidity dependence arises post cellular internalization during intracellular maturation of phagosomes. Together, these results reveal a complex interplay in regulation of innate immunity by biophysical cues and may ultimately offer new insights to intervene with macrophage functions therapeutically.