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.
Single-cell chromatin maps reveal heterogeneous macrophage polarization states
Cell cycle coincides with heterogeneity and alters macrophage plasticity to polarizing cytokines
Macrophage polarization is a cell cycle phase-dependent immunological process
S-G2/M-biased gene expression is linked to tissue remodeling and detected in proliferating macrophages during muscle regeneration
Competing Interest Statement
J.A.B. is a consultant for Immunai. A.T.S. is a founder of Immunai and Cartography Biosciences and receives research funding from Allogene Therapeutics and Arsenal Biosciences. H.Y.C. is a co-founder of Accent Therapeutics, Boundless Bio and Cartography Biosciences, and an advisor to 10x Genomics, Arsenal Biosciences, and Spring Discovery.