Toll-like Receptor 4, Osteoblasts and Leukemogenesis; the Lesson from Acute Myeloid Leukemia

Abstract

Toll-like receptor 4 (TLR4) is a pattern-recognizing receptor that can bind exogenous and endogenous ligands. It is expressed by acute myeloid leukemia (AML) cells, several bone marrow stromal cells, and nonleukemic cells involved in inflammation. TLR4 can bind a wide range of endogenous ligands that are present in the bone marrow microenvironment. Furthermore, the TLR4-expressing nonleukemic bone marrow cells include various mesenchymal cells, endothelial cells, differentiated myeloid cells, and inflammatory/immunocompetent cells. Osteoblasts are important stem cell supporting cells localized to the stem cell niches, and they support the proliferation and survival of primary AML cells. These supporting effects are mediated by the bidirectional crosstalk between AML cells and supportive osteoblasts through the local cytokine network. Finally, TLR4 is also important for the defense against complicating infections in neutropenic patients, and it seems to be involved in the regulation of inflammatory and immunological reactions in patients treated with allogeneic stem cell transplantation. Thus, TLR4 has direct effects on primary AML cells, and it has indirect effects on the leukemic cells through modulation of their supporting neighboring bone marrow stromal cells (i.e., modulation of stem cell niches, regulation of angiogenesis). Furthermore, in allotransplant recipients TLR4 can modulate inflammatory and potentially antileukemic immune reactivity. The use of TLR4 targeting as an antileukemic treatment will therefore depend both on the biology of the AML cells, the biological context of the AML cells, aging effects reflected both in the AML and the stromal cells and the additional antileukemic treatment combined with HSP90 inhibition.

Inflammatory response mediates cross-talk with immune function and reveals clinical features in acute myeloid leukemia

“…We identified several core molecules in DEGs, such as TLR4, SRC, ITGAM and CTSB, through the PPI network. Among them, the expression of TLR4 is associated with poor prognosis and can be inhibited with chemosensitizing and/or direct anti-leukemia effects [ 22–24 ]; knockdown of CTSB can inhibit the proliferation and tumorigenesis of the AML cell line HL-60 [ 25 ], which is also a poor prognostic factor for childhood AML [ 26 ]; SRC is a signaling mediator that activates STAT5 in FLT3-ITD-positive AML patients [ 27 ], and its overexpression also affects the sensitivity of FLT3-ITD kinase inhibitor and the pathway of acquired resistance [ 28 ]; ITGAM is a risk factor for autoimmune diseases such as systemic lupus erythematosus [ 29 ], but the mechanism associated with AML is less studied. Therefore, these molecules have potential as therapeutic targets for AML, but further exploration is required.…”

Pretransplant Systemic Lipidomic Profiles in Allogeneic Stem Cell Transplant Recipients

“…Various lipid classes and individual lipid metabolites are not only important for cellular metabolism, they are also important regulators of cellular proliferation and survival through their function as extracellular signaling molecules that bind to specific cellular receptors or modulate intracellular signaling through their molecular interactions in cellular membranes (e.g., anchoring of cell surface membrane molecules) [ 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 ]. Furthermore, pretransplant biological characteristics have an impact on prognosis/survival after allogeneic stem cell transplantation [ 13 ], and lipid metabolites also seem to be involved in the regulation of proliferation and survival of myeloid malignant cells [ 43 , 44 ].…”

Patients with Bacterial Sepsis Are Heterogeneous with Regard to Their Systemic Lipidomic Profiles

“…Lysophosphatidylcholines are ligands for TLR2 and TLR4 and possibly also for the G2A and GPR4 receptors. Ligation of TLR2/4 will often increase the release of proinflammatory cytokines (e.g., by monocytes) [ 61 , 62 ]. Lysophosphatidylcholines modulate monocytes and T-cell chemotaxis through G2A ligation, whereas endothelial cells are modulated through the ligation of the GPR4 to express higher levels of adhesion molecules, microvessel permeability is altered and chemotaxis of immunocompetent/inflammatory cells is probably altered [ 63 , 64 , 65 , 66 , 67 , 68 ].…”