Deconstructing inflammatory memory across tissue set points using cell circuit motifs

Tissue ecosystems are cellular communities that maintain set points through a network of intercellular interactions. We position health and chronic inflammatory disease as alternative stable set points that are (1) robust to perturbation and (2) capable of adaptation and memory. Inflammatory memory, which is the storage of prior experience to durably influence future responsiveness, is central to how tissue ecosystems may be pushed past tipping points that stabilize disease over health. Here, we develop a reductionist framework of circuit motifs that recur in tissue set points. In type 2 immunity, we distinctly find the emergence of 2-cell positive feedback motifs. In contrast, directional motif relays and 3-cell networks feature more prominently in type 1 and 17 responses. We propose that these differences guide the ecologic networks established after surpassing tipping points and associate closely with therapeutic responsiveness. We highlight opportunities to improve our current knowledge of how circuit motifs interact when building toward tissue-level networks across adaptation and memory. By developing new tools for circuit motif nomination and applying them to temporal profiling of tissue ecosystems, we hope to dissect the stability of the chronic inflammatory set point and open therapeutic avenues for rewriting memory to restore health.