Abstract
Functional toll-like receptors (TLRs) could modulate anti-tumor effects by activating inflammatory cytokines and the cytotoxic T-cells response. However, excessive TLR expression could promote tumor progression, since TLR-induced inflammation might stimulate cancer cells expansion into the microenvironment. Myd88 is involved in activation NF-κB through TLRs downstream signaling, hence in the current study we provided, for the first time, a complex characterization of expression of TLR2, TLR4, TLR7, TLR9, and MYD88 as well as their splicing forms in two distinct compartments of the microenvironment of chronic lymphocytic leukemia (CLL): peripheral blood and bone marrow. We found correlations between MYD88 and TLRs expressions in both compartments, indicating their relevant cooperation in CLL. The MYD88 expression was higher in CLL patients compared to healthy volunteers (HVs) (0.1780 vs. 0.128, p < 0.0001). The TLRs expression was aberrant in CLL compared to HVs. Analysis of survival curves revealed a shorter time to first treatment in the group of patients with low level of TLR4(3) expression compared to high level of TLR4(3) expression in bone marrow (13 months vs. 48 months, p = 0.0207). We suggest that TLRs expression is differentially regulated in CLL but is similarly shared between two distinct compartments of the microenvironment.
Highlights
Chronic lymphocytic leukemia (CLL) is a disease with the accumulation of aberrant B cells in peripheral blood as well as proliferation and accumulation of CLL cells in the bone marrow and peripheral lymphoid organs
The expression of TLR2, TLR7, TLR9 and splicing variants of TLR4 was confirmed in peripheral blood mononuclear cells (PBMC) in CLL patients as well as in healthy volunteers (HVs)
The expression of TLR7 and TLR9 was significantly higher in CLL patients compared to HVs (0.4790 vs. 0.1877, p < 0.0001), (0.3735 vs. 0.1066, p < 0.0001), respectively (Figure 1B,C)
Summary
Chronic lymphocytic leukemia (CLL) is a disease with the accumulation of aberrant B cells in peripheral blood as well as proliferation and accumulation of CLL cells in the bone marrow and peripheral lymphoid organs. TLRs expression is highly up-regulated through B-cell receptor (BCR) triggering of naive B-cells, indicating synergism between TLR and BCR leading to B-cell proliferation as well as differentiation [9]. All TLRs downstream signaling pathways except TLR3 are conducted by adaptor molecule Myd (myeloid differentiation primary response protein 88). It has been proven that TLRs types including 5, 7, 8, 9, 11 initiate the Myd88-dependent pathway directly. Myd88-dependent signaling pathway through TLRs types 1, 2, 4, 6 involves TIR—domaincontaining adaptor protein (TIRAP). TLR3 and TLR4 initiate an alternative pathway which is MyD88-independent by recruiting TIR-domain-containing adaptor protein, inducing IFN-β (TRIF) [10]. TLR-dependent signals could be involved in the regulation of B lymphocytes function by inducing TLR tolerance or auto-reactivity promotion [11]. The majority of data emphasized the role of adaptive immune receptors, including BCR, in the pathogenesis and progression of the disease [13,14,15]
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