Macrophage inflammatory and regenerative response periodicity is programmed by cell cycle and chromatin state

Summary

Cell cycle (CC) is a fundamental biological process with robust, cyclical gene expression programs to facilitate cell division. In the immune system, a productive immune response requires the expansion of pathogen-responsive cell types, but whether CC also confers unique gene expression programs that inform the subsequent immunological response remains unclear. Here we demonstrate that single macrophages adopt different plasticity states in CC, which is a major source of heterogeneity in response to polarizing cytokines. Specifically, macrophage plasticity to interferon gamma (IFNG) is substantially reduced, while interleukin 4 (IL-4) can induce S-G2/M-biased gene expression. Additionally, IL-4 polarization shifts the CC-phase distribution of the population towards G2/M phase, providing a mechanism for reduced IFNG-induced repolarization. Finally, we show that macrophages express tissue remodeling genes in the S-G2/M-phases of CC, that can be also detected in vivo during muscle regeneration. Therefore, macrophage inflammatory and regenerative responses are gated by CC in a cyclical phase-dependent manner.