TLR7/8 agonist treatment induces an increase in bone marrow resident dendritic cells and hematopoietic progenitor expansion and mobilization

Li, Sidan; Yao, Juo‐Chin; Li, Justin T.; Schmidt, Amy P.; Link, Daniel C.

doi:10.1016/j.exphem.2021.02.001

Cited by 9 publications

(8 citation statements)

References 86 publications

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“…There is accumulating evidence suggesting that TLR signals play an important role in the regulation of hematopoietic stem/progenitor cells (HSPCs). TLR7/8 agonist treatment increases bone marrow resident DCs as well as hematopoietic progenitor expansion and mobilization [ 125 ].…”

Section: The Tlr7/8 Signaling Pathwaymentioning

confidence: 99%

Targeting toll-like receptor 7/8 for immunotherapy: recent advances and prospectives

Sun

Zhang

et al. 2022

Biomark Res

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Toll-like receptors (TLRs) are a large family of proteins that are expressed in immune cells and various tumor cells. TLR7/8 are located in the intracellular endosomes, participate in tumor immune surveillance and play different roles in tumor growth. Activation of TLRs 7 and 8 triggers induction of a Th1 type innate immune response in the highly sophisticated process of innate immunity signaling with the recent research advances involving the small molecule activation of TLR 7 and 8. The wide range of expression and clinical significance of TLR7/TLR8 in different kinds of cancers have been extensively explored. TLR7/TLR8 can be used as novel diagnostic biomarkers, progression and prognostic indicators, and immunotherapeutic targets for various tumors. Although the mechanism of action of TLR7/8 in cancer immunotherapy is still incomplete, TLRs on T cells are involved in the regulation of T cell function and serve as co-stimulatory molecules and activate T cell immunity. TLR agonists can activate T cell-mediated antitumor responses with both innate and adaptive immune responses to improve tumor therapy. Recently, novel drugs of TLR7 or TLR8 agonists with different scaffolds have been developed. These agonists lead to the induction of certain cytokines and chemokines that can be applied to the treatment of some diseases and can be used as good adjutants for vaccines. Furthermore, TLR7/8 agonists as potential therapeutics for tumor-targeted immunotherapy have been developed. In this review, we summarize the recent advances in the development of immunotherapy strategies targeting TLR7/8 in patients with various cancers and chronic hepatitis B.

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Section: The Tlr7/8 Signaling Pathwaymentioning

confidence: 99%

Targeting toll-like receptor 7/8 for immunotherapy: recent advances and prospectives

Sun

Zhang

et al. 2022

Biomark Res

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“…They also demonstrated that depletion of DCs induces the mobilization of HSPCs from the BM by acting on the integrity of and chemokine expression by the vascular niches [ 33 ]. These findings also suggest a crosstalk between DCs and HSPCs, which is further supported by the fact that treatment of mice with the TLR7/8 agonist R848 directly affects the behavior and function of HSPCs and induces an expansion of the number of BM-resident DCs [ 34 ]. Our findings in this study take this crosstalk between HSPCs and DCs one step further, as we show that BM-resident DCs are particularly capable of taking up fungal antigens and subsequently skew hematopoiesis towards increased production of neutrophils in a G-CSF dependent manner.…”

Section: Discussionmentioning

confidence: 94%

Bone Marrow Harbors a Unique Population of Dendritic Cells with the Potential to Boost Neutrophil Formation upon Exposure to Fungal Antigen

Goedhart

Slot

Pascutti

et al. 2021

Cells

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Apart from controlling hematopoiesis, the bone marrow (BM) also serves as a secondary lymphoid organ, as it can induce naïve T cell priming by resident dendritic cells (DC). When analyzing DCs in murine BM, we uncovered that they are localized around sinusoids, can (cross)-present antigens, become activated upon intravenous LPS-injection, and for the most part belong to the cDC2 subtype which is associated with Th2/Th17 immunity. Gene-expression profiling revealed that BM-resident DCs are enriched for several c-type lectins, including Dectin-1, which can bind beta-glucans expressed on fungi and yeast. Indeed, DCs in BM were much more efficient in phagocytosis of both yeast-derived zymosan-particles and Aspergillus conidiae than their splenic counterparts, which was highly dependent on Dectin-1. DCs in human BM could also phagocytose zymosan, which was dependent on β1-integrins. Moreover, zymosan-stimulated BM-resident DCs enhanced the differentiation of hematopoietic stem and progenitor cells towards neutrophils, while also boosting the maintenance of these progenitors. Our findings signify an important role for BM DCs as translators between infection and hematopoiesis, particularly in anti-fungal immunity. The ability of BM-resident DCs to boost neutrophil formation is relevant from a clinical perspective and contributes to our understanding of the increased susceptibility for fungal infections following BM damage.

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“…Other analyses revealed that many TLRs such as TLR9 and TLR10 were mostly linked to CD19+ B-cells, whereas others—TLR2, TLR4, TLR8—were expressed to the utmost in CD14+ mononuclear cells [ 55 ]. TLR7 and TLR8 can primarily be found in the myeloid cell population, including neutrophils, monocytes, and DCs with a scarce expression of hematopoietic stem and progenitor cells (HSPCs) [ 56 ]. Human pDC mainly expresses TLR7 and TLR9, whereas mDC expresses most TLR except TLR7, TLR8, and TLR9 [ 54 ].…”

Section: Toll-like Receptors and Hematologymentioning

confidence: 99%

“…TLR signaling is able to have an influence over HSPCs both by cell autonomous and cell non-autonomous mechanisms [ 57 ]. Firsthand stimulation of TLR2, TLR4, and TLR7/8 causes multipotent HSPCs, common myeloid progenitors (CMPs), and granulocyte–macrophage progenitors (GMPs) to convert to monocytes, macrophages, and DCs at the cost of other progenitors [ 51 , 53 , 56 ]. CD34+ cells incubated with TLR7/8-specific agonists such as small interfering RNAs (siRNA-27), R848 (resiquimod), and loxoribine can differentiate into myeloid cells (early as well as late granulo-monocytic progenitor cells) [ 51 , 53 , 54 ].…”

Section: Toll-like Receptors and Hematologymentioning

confidence: 99%

“…A significant cell population of the CD34+ progenitor increased the expression of CD11c (deliberated as one of the markers of myeloid DC in humans) and CD13 (the early myeloid marker) [ 51 ]. Other studies showed that treatment with R848 induces considerable heightening in bone marrow (BM) resident cDC, a lowering in the common dendritic cells’ progenitors and pre-DCs, and upregulation of CD83 (DC activation marker); treatment prompted an expansion of phenotypic HSC with a decreased repopulating potential and HSPC mobilization [ 56 ]. Another study found that although TLR-induced lineage skewing of upstream progenitors can give rise to multiple cells, in the case of BM DC-restricted progenitors (CDPs) TLR induction results in their mobilization via down-regulation of chemokine receptor CXCR4 expression and recruitment to lymph nodes through up-regulation of chemokine receptor CCR7 expression [ 53 ].…”

Section: Toll-like Receptors and Hematologymentioning

confidence: 99%

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The Role of TRL7/8 Agonists in Cancer Therapy, with Special Emphasis on Hematologic Malignancies

et al. 2023

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Toll-like receptors (TLR) belong to the pattern recognition receptors (PRR). TLR7 and the closely correlated TLR8 affiliate with toll-like receptors family, are located in endosomes. They recognize single-stranded ribonucleic acid (RNA) molecules and synthetic deoxyribonucleic acid (DNA)/RNA analogs—oligoribonucleotides. TLRs are primarily expressed in hematopoietic cells. There is compiling evidence implying that TLRs also direct the formation of blood cellular components and make a contribution to the pathogenesis of certain hematopoietic malignancies. The latest research shows a positive effect of therapy with TRL agonists on the course of hemato-oncological diseases. Ligands impact activation of antigen-presenting cells which results in production of cytokines, transfer of mentioned cells to the lymphoid tissue and co-stimulatory surface molecules expression required for T-cell activation. Toll-like receptor agonists have already been used in oncology especially in the treatment of dermatological neoplastic lesions. The usage of these substances in the treatment of solid tumors is being investigated. The present review discusses the direct and indirect influence that TLR7/8 agonists, such as imiquimod, imidazoquinolines and resiquimod have on neoplastic cells and their promising role as adjuvants in anticancer vaccines.

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TLR7/8 agonist treatment induces an increase in bone marrow resident dendritic cells and hematopoietic progenitor expansion and mobilization

Cited by 9 publications

References 86 publications

Targeting toll-like receptor 7/8 for immunotherapy: recent advances and prospectives

Targeting toll-like receptor 7/8 for immunotherapy: recent advances and prospectives

Bone Marrow Harbors a Unique Population of Dendritic Cells with the Potential to Boost Neutrophil Formation upon Exposure to Fungal Antigen

The Role of TRL7/8 Agonists in Cancer Therapy, with Special Emphasis on Hematologic Malignancies

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