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

Bence Daniel; Julia A Belk; Stefanie L Meier; Andy Y Chen; Katalin Sandor; Zsolt Czimmerer; Zsofia Varga; Krisztian Bene; Frank A Buquicchio; Yanyan Qi; Hugo Kitano; Joshua R Wheeler; Deshka S Foster; Michael Januszyk; Michael T Longaker; Howard Y Chang; Ansuman T Satpathy

doi:10.1016/j.molcel.2022.11.017

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

Mol Cell. 2023 Jan 5;83(1):121-138.e7. doi: 10.1016/j.molcel.2022.11.017. Epub 2022 Dec 14.

Authors

Bence Daniel¹, Julia A Belk², Stefanie L Meier³, Andy Y Chen⁴, Katalin Sandor⁵, Zsolt Czimmerer⁶, Zsofia Varga⁷, Krisztian Bene⁷, Frank A Buquicchio⁸, Yanyan Qi⁹, Hugo Kitano¹⁰, Joshua R Wheeler¹¹, Deshka S Foster¹², Michael Januszyk¹², Michael T Longaker¹³, Howard Y Chang¹⁴, Ansuman T Satpathy¹⁵

Affiliations

¹ Department of Pathology, Stanford University, Stanford, CA 94305, USA; Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA. Electronic address: [email protected].
² Department of Pathology, Stanford University, Stanford, CA 94305, USA; Department of Computer Science, Stanford University, Stanford, CA 94305, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA.
³ Department of Pathology, Stanford University, Stanford, CA 94305, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA.
⁴ Department of Pathology, Stanford University, Stanford, CA 94305, USA; Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA.
⁵ Department of Pathology, Stanford University, Stanford, CA 94305, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA.
⁶ Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen 4032, Hungary; Institute of Genetics, Biological Research Centre, Eötvös Loránd Research Network, Szeged 6726, Hungary.
⁷ Department of Biochemistry and Molecular Biology, University of Debrecen, Debrecen 4032, Hungary.
⁸ Department of Pathology, Stanford University, Stanford, CA 94305, USA; Program in Immunology, Stanford University, Stanford, CA, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA.
⁹ Department of Pathology, Stanford University, Stanford, CA 94305, USA.
¹⁰ Department of Computer Science, Stanford University, Stanford, CA 94305, USA.
¹¹ Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA.
¹² Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Stanford University, Stanford, CA 94305, USA; Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹³ Hagey Laboratory for Pediatric Regenerative Medicine, Division of Plastic and Reconstructive Surgery, Stanford University, Stanford, CA 94305, USA; Department of Surgery, Stanford University School of Medicine, Stanford, CA 94305, USA; Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305, USA.
¹⁴ Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA. Electronic address: [email protected].
¹⁵ Department of Pathology, Stanford University, Stanford, CA 94305, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA 94129, USA; Program in Immunology, Stanford University, Stanford, CA, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA 94158, USA. Electronic address: [email protected].

Abstract

Cell cycle (CC) facilitates cell division via robust, cyclical gene expression. Protective immunity requires the expansion of pathogen-responsive cell types, but whether CC confers unique gene expression programs that direct the subsequent immunological response remains unclear. Here, we demonstrate that single macrophages (MFs) adopt different plasticity states in CC, which leads to heterogeneous cytokine-induced polarization, priming, and repolarization programs. Specifically, MF plasticity to interferon gamma (IFNG) is substantially reduced during S-G2/M, whereas interleukin 4 (IL-4) induces S-G2/M-biased gene expression, mediated by CC-biased enhancers. Additionally, IL-4 polarization shifts the CC-phase distribution of MFs toward the G2/M phase, providing a subpopulation-specific mechanism for IL-4-induced, dampened IFNG responsiveness. Finally, we demonstrate CC-dependent MF responses in murine and human disease settings in vivo, including Th2-driven airway inflammation and pulmonary fibrosis, where MFs express an S-G2/M-biased tissue remodeling gene program. Therefore, MF inflammatory and regenerative responses are gated by CC in a cyclical, phase-dependent manner.

Keywords: cell cycle; macrophage plasticity; macrophage polarization; single-cell epigenomics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Cycle / genetics
Cell Division
Chromatin* / genetics
Chromatin* / metabolism
Humans
Interferon-gamma / genetics
Interferon-gamma / pharmacology
Interleukin-4* / genetics
Interleukin-4* / pharmacology
Macrophages / metabolism
Mice

Substances

Interleukin-4
Chromatin
Interferon-gamma

Abstract

Publication types

MeSH terms

Substances

Grants and funding