Dual Feedforward Loops Modulate Type I Interferon Responses and Induce Selective Gene Expression during TLR4 Activation

Although the dynamic features of type I coherent feedforward loop (C1-FFL) has been well studied, how C1-FFL shapes cell-to-cell heterogeneity remains unclear. Here, we found that C1-FFL with OR logic serves as “noise reducer,” whereas C1-FFL with AND logic functions as “noise propagator” to fine-tune the heterogeneity of signaling molecule's activation. Within Toll-like receptor 4 (TLR4) signaling pathway, we demonstrated that MyD88 together with TRIF generates a C1-FFL to control TBK1 phosphorylation and reduce its cell-to-cell heterogeneity, whereas noisy TRIF activation induced high heterogeneity of IRF3 activation through another C1-FFL. We further developed a mathematical model with dual C1-FFLs to uncover how MyD88 and TRIF encoded differential dynamics for TBK1 and IRF3 activation. Integration of dual FFLs drives MyD88-TBK1 axis to determine the specificity of IFN-stimulated genes transcription. Collectively, our work elucidates a paradigm that tunable TLR4-mediated type I IFN responses are subtly controlled by dual FFLs.