@article{8896c04c8d664694b1d00f5ebe81ca29,
title = "IL-1β expression in bone marrow dendritic cells is induced by TLR2 agonists and regulates HSC function",
abstract = "Hematopoietic stem/progenitor cells (HSPCs) reside in localized microenvironments, or niches, in the bone marrow that provide key signals regulating their activity. A fundamental property of hematopoiesis is the ability to respond to environmental cues such as inflammation. How these cues are transmitted to HSPCs within hematopoietic niches is not well established. Here, we show that perivascular bone marrow dendritic cells (DCs) express a high basal level of Toll-like receptor-1 (TLR1) and TLR2. Systemic treatment with a TLR1/2 agonist induces HSPC expansion and mobilization. It also induces marked alterations in the bone marrow microenvironment, including a decrease in osteoblast activity and sinusoidal endothelial cell numbers. TLR1/2 agonist treatment of mice in which Myd88 is deleted specifically in DCs using Zbtb46-Cre show that the TLR1/2-induced expansion of multipotent HPSCs, but not HSPC mobilization or alterations in the bone marrow microenvironment, is dependent on TLR1/2 signaling in DCs. Interleukin-1β (IL-1β) is constitutively expressed in both murine and human DCs and is further induced after TLR1/2 stimulation. Systemic TLR1/2 agonist treatment of Il1r1−/− mice show that TLR1/2-induced HSPC expansion is dependent on IL-1β signaling. Single-cell RNA-sequencing of low-risk myelodysplastic syndrome bone marrow revealed that IL1B and TLR1 expression is increased in DCs. Collectively, these data suggest a model in which TLR1/2 stimulation of DCs induces secretion of IL-1β and other inflammatory cytokines into the perivascular niche, which in turn, regulates multipotent HSPCs. Increased DC TLR1/2 signaling may contribute to altered HSPC function in myelodysplastic syndrome by increasing local IL-1β expression.",
author = "Sidan Li and Yao, {Juo Chin} and Oetjen, {Karolyn A.} and Krambs, {Joseph R.} and Jun Xia and Jingzhu Zhang and Schmidt, {Amy P.} and Helton, {Nichole M.} and Fulton, {Robert S.} and Heath, {Sharon E.} and Turnbull, {Isaiah R.} and Gabriel Mbalaviele and Ley, {Timothy J.} and Walter, {Matthew J.} and Link, {Daniel C.}",
note = "Funding Information: To assess the impact of DC IL-1β on HSPCs, we cultured sorted wild-type HSCs (LSK-SLAM cells) with CM from bone marrow–derived DCs stimulated with PAM3CSK4 (Figure 6J). Of note, we confirmed that PAM3CSK4 treatment strongly induced IL-1β protein levels in DC CM (Figure 6K). DC CM supported the expansion of HSPCs that was significantly accentuated in cultures with PAM3CSK4–treated DC CM (Figure 6L; supplemental Figure 7). Importantly, the augmented HSC proliferation induced by PAM3CSK4–treated DC CM was abrogated by the addition of the IL-1 receptor antagonist anakinra. Collectively, these data suggest that PAM3CSK4 treatment induces an expansion of multipotent HSPCs, at least in part, by increasing IL-1β expression in bone marrow DCs.This study was supported by the National Institutes of Health, National Cancer Institute (PO1CA101937, D.C.L. and M.J.W.), the Taub Foundation Grants Program for Myelodysplastic Syndromes (MDS) Research (D.C.L.), the Siteman Cancer Center and the Foundation for Barnes-Jewish Hospital Cancer Fund (M.J.W.), and the Edward P. Evans Foundation. G.M. is supported by the National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR076758), and the National Institute of Allergy and Infectious Diseases (AI161022). Contribution: S.L. J.-C.Y. K.A.O. and D.C.L. conceived the study; S.L. J.-C.Y. and K.A.O. performed the majority of the experiments and analyzed the data; J.Z. and A.P.S. helped with transplantation and sample collection; K.A.O. J.X. J.R.K. N.M.H. R.S.F. S.E.H. T.J.L. and M.J.W. provided tissue samples or assisted with RNA-sequencing analyses; I.R.T. and G.M. provided essential experimental reagents; and S.L. J.-C.Y. K.A.O. and D.C.L. wrote the paper. Funding Information: This study was supported by the National Institutes of Health , National Cancer Institute ( PO1CA101937 , D.C.L. and M.J.W.), the Taub Foundation Grants Program for Myelodysplastic Syndromes ( MDS ) Research (D.C.L.), the Siteman Cancer Center and the Foundation for Barnes-Jewish Hospital Cancer Fund (M.J.W.), and the Edward P. Evans Foundation . G.M. is supported by the National Institutes of Health , National Institute of Arthritis and Musculoskeletal and Skin Diseases ( AR076758 ), and the National Institute of Allergy and Infectious Diseases ( AI161022 ). Publisher Copyright: {\textcopyright} 2022 The American Society of Hematology",
year = "2022",
month = oct,
day = "6",
doi = "10.1182/blood.2022016084",
language = "English",
volume = "140",
pages = "1607--1620",
journal = "Blood",
issn = "0006-4971",
number = "14",
}