Functional heterogeneity of inflammatory signaling

Pawel Paszek (University of Manchester)

Conference Room A, Schuster Building,

Robust pathogen recognition and effector cytokine production underlie propagation of inflammation.  We found that the toll-like receptor activation in macrophages resulted in an analogue signal-processing paradigm, in which NF-κB dependent TNFα cytokine output is fine-tuned by the level of pathogen infection in single cells.  A local tissue environment enforced a requirement for macrophages to be positioned around one cell width apart in order to propagage TNFα signalling.  Responses of single macrophage and tissue cells exhibited substantial heterogeneity, which may arise from the stochastic transcription or multiple cellular states existing in isogenic populations.  It has often been thought that dynamic biological systems may have evolved to maximise robustness through cell-to-cell coordination and heterogeneity.  We hypothesize that cellular heterogeneity is an inherent design motif of the inflammatory response that may avoid out-of-control cellular activation.

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