Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities

Xiaofei Li; Hui Wang; Xiang Yu; Gundappa Saha; Lydia Kalafati; Charalampos Ioannidis; Ioannis Mitroulis; Mihai G Netea; Triantafyllos Chavakis; George Hajishengallis

doi:10.1016/j.cell.2022.03.043

Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities

Cell. 2022 May 12;185(10):1709-1727.e18. doi: 10.1016/j.cell.2022.03.043. Epub 2022 Apr 27.

Authors

Affiliations

¹ Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
² Joint International Research Laboratory of Metabolic and Developmental Sciences, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai 200240, China; Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
³ Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, Germany.
⁴ Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, Germany; First Department of Internal Medicine and Department of Haematology, Democritus University of Thrace, 681 00 Alexandroupolis, Greece.
⁵ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen 6525 XZ, the Netherlands; Department of Immunology and Metabolism, Life and Medical Science Institute, University of Bonn, 53115 Bonn, Germany.
⁶ Institute for Clinical Chemistry and Laboratory Medicine, Faculty of Medicine, Technische Universität Dresden, 01307 Dresden, Germany; Centre for Cardiovascular Science, University of Edinburgh, Edinburgh EH16 4TJ, UK. Electronic address: triantafyllos.chavakis@uniklinikum-dresden.de.
⁷ Department of Basic and Translational Sciences, Laboratory of Innate Immunity and Inflammation, Penn Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: geoh@upenn.edu.

Abstract

Bone marrow (BM)-mediated trained innate immunity (TII) is a state of heightened immune responsiveness of hematopoietic stem and progenitor cells (HSPC) and their myeloid progeny. We show here that maladaptive BM-mediated TII underlies inflammatory comorbidities, as exemplified by the periodontitis-arthritis axis. Experimental-periodontitis-related systemic inflammation in mice induced epigenetic rewiring of HSPC and led to sustained enhancement of production of myeloid cells with increased inflammatory preparedness. The periodontitis-induced trained phenotype was transmissible by BM transplantation to naive recipients, which exhibited increased inflammatory responsiveness and disease severity when subjected to inflammatory arthritis. IL-1 signaling in HSPC was essential for their maladaptive training by periodontitis. Therefore, maladaptive innate immune training of myelopoiesis underlies inflammatory comorbidities and may be pharmacologically targeted to treat them via a holistic approach.

Keywords: arthritis; bone marrow transplantation; comorbidities; epigenetic rewiring; hematopoietic stem and progenitor cells; inflammation; myelopoiesis; periodontitis; trained immunity.

Publication types

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

MeSH terms

Animals
Arthritis*
Hematopoietic Stem Cells
Immunity, Innate
Mice
Myelopoiesis
Periodontitis*

Abstract

Publication types

MeSH terms

Grants and funding