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.

中文翻译：

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使用细胞回路基序解构组织设定点的炎症记忆。


组织生态系统是通过细胞间相互作用网络维持设定点的细胞群落。我们将健康和慢性炎症性疾病定位为替代的稳定设定点，这些设定点 （1） 对扰动具有稳健性，并且 （2） 能够适应和记忆。炎症记忆是储存先前的经验以持久影响未来的反应性，是组织生态系统如何被推过稳定疾病而不是健康的临界点的核心。在这里，我们开发了一个在组织设定点中重复出现的电路基序的还原论框架。在 2 型免疫中，我们清楚地发现 2 细胞正反馈基序的出现。相比之下，定向基序中继和 3 细胞网络在 1 型和 17 型反应中更为突出。我们建议这些差异指导在超过临界点后建立的生态网络，并与治疗反应密切相关。我们强调了提高我们目前对电路基序在跨适应和记忆构建组织水平网络时如何相互作用的认识的机会。通过开发用于电路基序提名的新工具并将其应用于组织生态系统的时间分析，我们希望剖析慢性炎症设定点的稳定性，并为重写记忆以恢复健康开辟治疗途径。