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Myeloid Innate Signaling Pathway Regulation by MALT1 Paracaspase Activity
Published on: January 7, 2019
Toll-like receptor stimulation in splenic marginal zone lymphoma can modulate cell signaling, activation and
Eleonora Fonte1, Andreas Agathangelidis2, Daniele Reverberi3
1Division of Experimental Oncology, IRCCS San Raffaele Scientific Institute, Milano, Italy Università degli studi di Pavia, Italy.
Abstract:
Recent studies on splenic marginal zone lymphoma identified distinct mutations in genes belonging to the B-cell receptor and Toll-like receptor signaling pathways, thus pointing to their potential implication in the biology of the disease. However, limited data is available regarding the exact role of TLRs. We aimed at characterizing the expression pattern of TLRs in splenic marginal zone lymphoma cells and their functional impact on the activation, proliferation and viability of malignant cells in vitro. Cells expressed significant levels of TLR1, TLR6, TLR7, TLR8, TLR9 and TLR10 mRNA; TLR2 and TLR4 showed a low, variable pattern of expression among patients whereas TLR3 and TLR5 mRNAs were undetectable; mRNA specific for TLR signaling molecules and adapters was also expressed. At the protein level, TLR1, TLR6, TLR7, TLR9 and TLR10 were detected. Stimulation of TLR1/2, TLR2/6 and TLR9 with their respective ligands triggered the activation of IRAK kinases, MAPK and NF-κB signaling pathways, and the induction of CD86 and CD25 activation molecules, although in a heterogeneous manner among different patient samples. TLR-induced activation and cell viability were also inhibited by a specific IRAK1/4 inhibitor, thus strongly supporting the specific role of TLR signaling in these processes. Furthermore, TLR2/6 and TLR9 stimulation also significantly increased cell proliferation. In conclusion, we demonstrate that splenic marginal zone lymphoma cells are equipped with functional TLR and signaling molecules and that the stimulation of TLR1/2, TLR2/6 and TLR9 may play a role in regulating disease pathobiology, likely promoting the expansion of the neoplastic clone.
Insights
Splenic marginal zone lymphoma cells express functional Toll-like receptors (TLRs). TLR stimulation activates key signaling pathways, promoting lymphoma cell activation, viability, and proliferation, suggesting a role in disease progression.
Area of Science:
- Hematology
- Immunology
- Oncology
Background:
- Splenic marginal zone lymphoma (SMZL) studies reveal mutations in B-cell receptor and Toll-like receptor (TLR) signaling pathways.
- Limited data exists on the specific role of TLRs in SMZL pathogenesis.
Purpose of the Study:
- To characterize TLR expression in SMZL cells.
- To investigate the functional impact of TLRs on malignant cell activation, proliferation, and viability in vitro.
Main Methods:
- Quantification of TLR and signaling molecule mRNA and protein expression in SMZL cells.
- Stimulation of TLRs with specific ligands.
- Assessment of signaling pathway activation (IRAK, MAPK, NF-κB) and expression of activation markers (CD86, CD25).
- Evaluation of cell proliferation and viability using a specific IRAK1/4 inhibitor.
Main Results:
- SMZL cells expressed significant levels of TLR1, TLR6, TLR7, TLR8, TLR9, and TLR10 mRNA and protein.
- TLR stimulation activated IRAK, MAPK, and NF-κB pathways, inducing CD86 and CD25.
- TLR stimulation increased cell proliferation and viability, effects inhibited by an IRAK1/4 inhibitor.
- Heterogeneous responses were observed across patient samples.
Conclusions:
- SMZL cells possess functional TLRs and associated signaling molecules.
- TLR stimulation, particularly via TLR1/2, TLR2/6, and TLR9, may contribute to SMZL pathobiology.
- TLR signaling likely promotes neoplastic clone expansion in SMZL.
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