Stimulus-specific responses in innate immunity: Multilayered regulatory circuits

Immune sentinel cells initiate immune responses to pathogens and tissue injury and are capable of producing highly stimulus-specific responses. Insight into the mechanisms underlying such specificity has come from the identification of regulatory factors and biochemical pathways, as well as the definition of signaling circuits that enable combinatorial and temporal coding of information. Here, we review the multi-layered molecular mechanisms that underlie stimulus-specific gene expression in macrophages. We categorize components of inflammatory and anti-pathogenic signaling pathways into five layers of regulatory control and discuss unifying mechanisms determining signaling characteristics at each layer. In this context, we review mechanisms that enable combinatorial and temporal encoding of information, identify recurring regulatory motifs and principles, and present strategies for integrating experimental and computational approaches toward the understanding of signaling specificity in innate immunity.