Innate immune cells fight against invading pathogens through an internalization process known as phagocytosis. The detection of pathogens and initiation of subsequent immune responses require the synergistic function between many sets of receptors at phagosome membranes. Understanding the interactions between the phagocytic receptors and how their interactions lead to signaling crosstalk is crucial for dissecting the pathogenesis of many infectious diseases and chronic inflammatory diseases. Because phagosomes are intracellular vesicular structures that are inaccessible from outside, phagosome signaling crosstalk has only been studied using indirect means, including immunofluorescence imaging, co-immunoprecipitation, and gene knockdown. All those methods suffer from major drawbacks. There remains a lack of direct evidence demonstrating the connection between interactions between receptors and their signaling crosstalk. To address this need, we developed a "geometric mutation" method that allows us to directly and physically manipulate receptor collaboration at phagosome membranes. By using specially fabricated particles, we physically decoupled Dectin-1 and TLR2 receptors and measured the corresponding immune responses of macrophage cells. Our results provide direct evidence revealing the role of Dectin-1 and TLR2 crosstalk in various steps of immune reactions.

"Geometric mutation" for decoupling receptor signaling crosstalk at phagosome membranes

255th National Meeting (2018)

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