TLR5 signaling in murine bone marrow induces hematopoietic progenitor cell proliferation and aids survival from radiation

Zhang, Benyue; Oyewole-Said, Damilola; Zou, Jun; Willliams, Ifor R.; Gewirtz, Andrew T.

doi:10.1182/bloodadvances.2017006981

Cited by 11 publications

(10 citation statements)

References 46 publications

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“…During steady-state normal hematopoiesis, HSCs generate functionally distinct lineage-biased multipotent progenitors (MPPs), with MPP2/3 and MPP4 populations predominantly sustaining myeloid and lymphoid lineages, respectively (Pietras et al, 2015). Stressful conditions such as infection, stress, or injury induce proinflammatory stimuli, which not only activate HSCs but also cause expansion of MPPs, in particular myeloid-biased MPP2/3 populations, thereby driving myeloid differentiation at the expense of HSC integrity (Essers et al, 2009;Pietras et al, 2016;Yamashita and Passegue, 2019;Zhang et al, 2017;Zhang et al, 2016). Consistent with the activation of proinflammatory pathways, we found that 8-12-wkold Ythdf2 CKO mice displayed expansion of HSCs and a concurrent increase in all four main subpopulations, namely MPP1-4 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function

Mapperley

Lagemaat

Lawson

et al. 2020

Journal of Experimental Medicine

111

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The mRNA N6-methyladenosine (m6A) modification has emerged as an essential regulator of normal and malignant hematopoiesis. Inactivation of the m6A mRNA reader YTHDF2, which recognizes m6A-modified transcripts to promote m6A-mRNA degradation, results in hematopoietic stem cell (HSC) expansion and compromises acute myeloid leukemia. Here we investigate the long-term impact of YTHDF2 deletion on HSC maintenance and multilineage hematopoiesis. We demonstrate that Ythdf2-deficient HSCs from young mice fail upon serial transplantation, display increased abundance of multiple m6A-modified inflammation-related transcripts, and chronically activate proinflammatory pathways. Consistent with the detrimental consequences of chronic activation of inflammatory pathways in HSCs, hematopoiesis-specific Ythdf2 deficiency results in a progressive myeloid bias, loss of lymphoid potential, HSC expansion, and failure of aged Ythdf2-deficient HSCs to reconstitute multilineage hematopoiesis. Experimentally induced inflammation increases YTHDF2 expression, and YTHDF2 is required to protect HSCs from this insult. Thus, our study positions YTHDF2 as a repressor of inflammatory pathways in HSCs and highlights the significance of m6A in long-term HSC maintenance.

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Section: Resultsmentioning

confidence: 99%

The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function

Mapperley

Lagemaat

Lawson

et al. 2020

Journal of Experimental Medicine

111

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“…Besides, NF-κB is the downstream of Toll-like receptors (TLRs) and mediates the radiation protection effect of several cytokines or small molecule drugs 56,57 . On the contrary, TGF-β/Smad pathway has been shown to sustain the quiescence of HSCs 21,58 .…”

Section: Discussionmentioning

confidence: 99%

Melanocortin/MC5R axis regulates the proliferation of hematopoietic stem cells in mice after ionizing radiation injury

et al. 2023

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Hematopoietic stem cells (HSCs) possess the great self-renewal and multidirectional differentiation ability, which contributes to the continuous generation of various blood cells. Although many intrinsic and extrinsic factors have been found to maintain HSC homeostasis, how to precisely regulate hematopoiesis under stress conditions is poorly understood. In this study, we show that melanocortin receptor 5 (MC5R) is abundantly expressed in hematopoietic stem progenitor cells (HSPCs). Using a MC5R knockout (MC5R-/-) mouse model, we observe that it is not essential for steady-state hematopoiesis. Interestingly, the levels of α-melanocyte stimulating hormone (α-MSH), an important sub-type of melanocortin, are elevated in serum and bone marrow, and the expression of MC5R is upregulated in HSPCs from mice after irradiation. MC5R deficiency aggravates irradiation-induced myelosuppression due to the impairment in the proliferation and reconstitution function of HSCs. Further investigations exhibit that melanocortin/MC5R axis regulates the proliferation of HSCs through activating the PI3K/AKT and MAPK pathways. More importantly, α-MSH treatment can significantly accelerate the hematopoietic recovery in irradiated mice. In conclusion, our data demonstrate that melanocortin/MC5R axis plays a crucial role in regulating HSC proliferation under stress, thus providing a promising strategy to promote hematopoietic regeneration when suffering from injury.

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“…Consistently, we observed in our experiments that Flagellin promoted MΦ differentiation in the lung, but not in blood or BM. Intraperitoneal injection of Flagellin was shown earlier to result in proliferation of myeloid-primed progenitor cells, termed MMP3 cells (Lin − Sca-1 + c-Kit + Flt-3 − CD150 − CD48 + ) ( 22 ), which are distinct from MO(D)Ps. It was not examined whether these cells expressed TLR5.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, it has been reported that systemic Flagellin administration drives rapid TLR5-dependent HSC cell proliferation and a great increase in multipotent progenitors. Neutrophils produced by these progenitors protected mice against total body irradiation ( 22 ). The generation of myeloid cells from hematopoietic progenitors fits in the concept of “emergency hematopoiesis.” Herein, myeloid cells are generated de novo from progenitors, to boost immune defense and tissue repair ( 23 ).…”

Section: Introductionmentioning

confidence: 99%

Flagellin/TLR5 Stimulate Myeloid Progenitors to Enter Lung Tissue and to Locally Differentiate Into Macrophages

et al. 2021

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Toll-like receptor 5 (TLR5) is the receptor of bacterial Flagellin. Reportedly, TLR5 engagement helps to combat infections, especially at mucosal sites, by evoking responses from epithelial cells and immune cells. Here we report that TLR5 is expressed on a previously defined bipotent progenitor of macrophages (MΦs) and osteoclasts (OCs) that resides in the mouse bone marrow (BM) and circulates at low frequency in the blood. In vitro, Flagellin promoted the generation of MΦs, but not OCs from this progenitor. In vivo, MΦ/OC progenitors were recruited from the blood into the lung upon intranasal inoculation of Flagellin, where they rapidly differentiated into MΦs. Recruitment of the MΦ/OC progenitors into the lung was likely promoted by the CCL2/CCR2 axis, since the progenitors expressed CCR2 and type 2 alveolar epithelial cells (AECs) produced CCL2 upon stimulation by Flagellin. Moreover, CCR2 blockade reduced migration of the MΦ/OC progenitors toward lung lavage fluid (LLF) from Flagellin-inoculated mice. Our study points to a novel role of the Flagellin/TLR5 axis in recruiting circulating MΦ/OC progenitors into infected tissue and stimulating these progenitors to locally differentiate into MΦs. The progenitor pathway to produce MΦs may act, next to monocyte recruitment, to fortify host protection against bacterial infection at mucosal sites.

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TLR5 signaling in murine bone marrow induces hematopoietic progenitor cell proliferation and aids survival from radiation

Abstract: Key Points Flagellin activates TLR5 signaling in mouse bone marrow and induces hematopoietic progenitor cell proliferation. Flagellin-induced MPP3 cells aid the survival of mice exposed to lethal irradiation.

Cited by 11 publications

References 46 publications

The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function

The mRNA m6A reader YTHDF2 suppresses proinflammatory pathways and sustains hematopoietic stem cell function

Melanocortin/MC5R axis regulates the proliferation of hematopoietic stem cells in mice after ionizing radiation injury

Flagellin/TLR5 Stimulate Myeloid Progenitors to Enter Lung Tissue and to Locally Differentiate Into Macrophages

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