Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities

• Published in: Cell Vol. 185; no. 10; pp. 1709 - 1727.e18
• Main Authors: Li, Xiaofei, Wang, Hui, Yu, Xiang, Saha, Gundappa, Kalafati, Lydia, Ioannidis, Charalampos, Mitroulis, Ioannis, Netea, Mihai G., Chavakis, Triantafyllos, Hajishengallis, George
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.05.2022
• Subjects: Animals; Arthritis; bone marrow; bone marrow transplantation; comorbidities; disease severity; epigenetic rewiring; epigenetics; hematopoietic stem and progenitor cells; Hematopoietic Stem Cells; Immunity, Innate; inflammation; innate immunity; interleukin-1; Mice; Myelopoiesis; Periodontitis; phenotype; progeny; trained immunity; comorbidities; arthritis; inflammation; myelopoiesis; periodontitis; hematopoietic stem and progenitor cells; epigenetic rewiring; trained immunity; bone marrow transplantation
• ISSN: 0092-8674; 1097-4172; 1097-4172
• DOI: 10.1016/j.cell.2022.03.043

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. [Display omitted] •Experimental periodontitis (EP) induces maladaptive trained myelopoiesis•EP-induced trained phenotype is transmissible by bone marrow transplantation•IL-1 signaling in hematopoietic progenitors mediates maladaptive training by EP•Maladaptively trained myelopoiesis links the periodontitis-arthritis comorbidity Trained innate immune responses contribute to pathology of a comorbid condition, as seen with arthritis after periodontitis in animal models.