TY - JOUR
T1 - Maladaptive innate immune training of myelopoiesis links inflammatory comorbidities
AU - Li, Xiaofei
AU - Wang, Hui
AU - Yu, Xiang
AU - Saha, Gundappa
AU - Kalafati, Lydia
AU - Ioannidis, Charalampos
AU - Mitroulis, Ioannis
AU - Netea, Mihai G.
AU - Chavakis, Triantafyllos
AU - Hajishengallis, George
N1 - Funding Information:
This work was supported by NIH grants ( DE029436 and DE031206 to G.H.; DE028561 to G.H. and T.C.) and the Deutsche Forschungsgemeinschaft ( SFB-TR 127 , A3 and SFB1181 , C7 to T.C.). T.C. was also supported by the British Heart Foundation Centre for Research Excellence at The University of Edinburgh ( RE/18/5/34216 ) and the “Sonderzuweisung zur Unterstützung profilbestimmender Struktureinheiten 2021” by the SMWK. M.G.N. is supported by a Spinoza grant from the Netherlands Organization for Scientific Research and a European Research Council Advanced Grant (# 833247 ). We thank Sylvia Grossklaus ( Institute for Clinical Chemistry and Laboratory Medicine , Technische Universität Dresden ) for technical assistance. The graphical abstract was created using BioRender.com .
Funding Information:
This work was supported by NIH grants (DE029436 and DE031206 to G.H.; DE028561 to G.H. and T.C.) and the Deutsche Forschungsgemeinschaft (SFB-TR 127, A3 and SFB1181, C7 to T.C.). T.C. was also supported by the British Heart Foundation Centre for Research Excellence at The University of Edinburgh (RE/18/5/34216) and the “Sonderzuweisung zur Unterstützung profilbestimmender Struktureinheiten 2021” by the SMWK. M.G.N. is supported by a Spinoza grant from the Netherlands Organization for Scientific Research and a European Research Council Advanced Grant (#833247). We thank Sylvia Grossklaus (Institute for Clinical Chemistry and Laboratory Medicine, Technische Universität Dresden) for technical assistance. The graphical abstract was created using BioRender.com. X.L. designed and performed research, analyzed and interpreted data, and co-wrote the manuscript; H.W. designed and performed research, analyzed and interpreted data, and contributed to writing; X.Y. performed experiments and analyzed data; G.S. performed experiments; L.K. and C.I. generated critical reagents; I.M. interpreted data; M.G.N. interpreted data and edited the manuscript; T.C. conceived and designed the study, interpreted data, and edited the manuscript; G.H. conceived and designed the study, supervised research, interpreted data, and wrote the manuscript. M.G.N. is the scientific founder and member of the Scientific Advisory Board of Trained Therapeutics and Discovery (TTxD). M.G.N. has two patents: US18/61935 (Targeted nanoimmunotherapy to increase trained immunity) and US18/61939 (Targeted nanoimmunotherapy for inhibition of trained immunity). The other authors declare no competing interests.
Publisher Copyright:
© 2022 Elsevier Inc.
PY - 2022/5/12
Y1 - 2022/5/12
N2 - 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.
AB - 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.
U2 - 10.1016/j.cell.2022.03.043
DO - 10.1016/j.cell.2022.03.043
M3 - Article
SN - 0092-8674
JO - Cell
JF - Cell
ER -