Wnt5a is a TLR2/4-ligand that induces tolerance in human myeloid cells

Mehmeti, Meliha; Bergenfelz, Caroline; Källberg, Eva; Millrud, Camilla Rydberg; Björk, Per; Ivars, Fredrik; Johansson‐Lindbom, Bengt; Kjellström, Sven; André, Ingemar; Leandersson, Karin

doi:10.1038/s42003-019-0432-4

Cited by 24 publications

(24 citation statements)

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“…Apart from cytokines, exosomes derived from stromal cells are also known for their protective effect on the cancer cells via juxtacrine signaling or due to delivery of exosomal miRNAs or other regulatory factors ferried in the lumen of the exosomes 27,28 . Recently, even Wnt5 has also been identified as a ligand involved in activate NF-kB signaling 29 . Wnt proteins are also known to be ferried on exosomes 30 .…”

Section: Discussionmentioning

confidence: 99%

Stromal cells downregulate miR-23a-5p to activate protective autophagy in acute myeloid leukemia

et al. 2019

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Complex molecular cross talk between stromal cells and the leukemic cells in bone marrow is known to contribute significantly towards drug-resistance. Here, we have identified the molecular events that lead to stromal cells mediated therapy-resistance in acute myeloid leukemia (AML). Our work demonstrates that stromal cells downregulate miR-23a-5p levels in leukemic cells to protect them from the chemotherapy induced apoptosis. Downregulation of miR-23a-5p in leukemic cells leads to upregulation of protective autophagy by targeting TLR2 expression. Further, autophagy inhibitors when used as adjuvants along with conventional drugs can improve drug sensitivity in vitro as well in vivo in a mouse model of leukemia. Our work also demonstrates that this mechanism of bone marrow stromal cell mediated regulation of miR-23a-5p levels and subsequent molecular events are relevant predominantly in myeloid leukemia. Our results illustrate the critical and dynamic role of the bone marrow microenvironment in modulating miRNA expression in leukemic cells which could contribute significantly to drug resistance and subsequent relapse, possibly through persistence of minimal residual disease in this environment.

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Section: Discussionmentioning

confidence: 99%

Stromal cells downregulate miR-23a-5p to activate protective autophagy in acute myeloid leukemia

et al. 2019

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“…Some indication that the latter apect might indeed be of importance comes from studies of macrophages stimulated with lipopolysaccharide (LPS), a major cell wall component of Gram-negative bacteria. Increased WNT5A expression has been noted in LPS-stimulated human monocytes, the human monocytic THP-1 cell line, as well as human bronchial epithelial BEAS-2B cells (19, 34, 53, 60, 61). LPS-induced WNT5A expression in human macrophages occured downstream of Toll-like receptor signaling and nuclear factor kappa B (NF-κB) activation, and was amplified by inflammatory cytokines such as tumor necrosis factor (TNF) and interferon γ (IFNγ) (19, 34, 60).…”

Section: Wnt Responses To Infectionmentioning

confidence: 99%

Functions of the WNT Signaling Network in Shaping Host Responses to Infection

et al. 2019

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It is well-established that aberrant WNT expression and signaling is associated with developmental defects, malignant transformation and carcinogenesis. More recently, WNT ligands have emerged as integral components of host responses to infection but their functions in the context of immune responses are incompletely understood. Roles in the modulation of inflammatory cytokine production, host cell intrinsic innate defense mechanisms, as well as the bridging of innate and adaptive immunity have been described. To what degree WNT responses are defined by the nature of the invading pathogen or are specific for subsets of host cells is currently not well-understood. Here we provide an overview of WNT responses during infection with phylogenetically diverse pathogens and highlight functions of WNT ligands in the host defense against infection. Detailed understanding of how the WNT network orchestrates immune cell functions will not only improve our understanding of the fundamental principles underlying complex immune response, but also help identify therapeutic opportunities or potential risks associated with the pharmacological targeting of the WNT network, as currently pursued for novel therapeutics in cancer and bone disorders.

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“…For each run, 2 µL of reconstituted sample was injected, which corresponded to 1.6 µL of the original wound fluid or plasma sample. For the evaluation of the sample preparation method, LC-MS/MS analyses were carried out on an Orbitrap Fusion Tribrid MS (Thermo Scientific) as described earlier 35 , with the following modifications. During the elution steps, the percentage of solvent B increased from 5% to 22% in the first 20 min, then increased to 20% in 85 min, then to 30% in 20 min, and to 90% in a further 5 minutes, where it was kept for 5 minutes.…”

Section: Lc-ms/ms Analysismentioning

confidence: 99%

Method development and characterization of the low molecular weight peptidome of human wound fluids

Plas

Cai

Petrlová

et al. 2020

Preprint

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Wound infections are significant challenges globally, and there is an unmet need for better diagnosis of wound healing status and infection. The wound healing process is characterized by proteolytic events that are the result of basic physiological processes involving coagulation and complement activation, but also dysfunctional activations by endogenous and bacterial proteases. Peptides, downstream reporters of these proteolytic actions, could therefore serve as a promising tool for diagnosis of wound healing and infection. In the present study, we demonstrate a method for the characterisation of the complete peptidome of human wound fluids. We compare acute non-infected wound fluids obtained post-surgery with plasma samples and find significantly higher protein and peptide numbers in wound fluids, which typically were also smaller in size as compared to plasma-derived peptides. Finally, we analyse wound fluids collected from dressings after facial skin graft surgery and compare three uninfected and normally healing surgical wounds with three inflamed and Staphylococcus aureus infected wounds. The results identify unique peptide patterns of various selected proteins including coagulation and complement factors, as well as proteases and antiproteinases. Together, the work defines a workflow for analysis of peptides derived from human wound fluids and demonstrate a proof-of-concept that such wound fluids can be used for analysis of qualitative differences of peptide patterns derived from wound fluids on larger patient cohorts, providing novel biomarkers for wound healing and infection.

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Wnt5a is a TLR2/4-ligand that induces tolerance in human myeloid cells

Cited by 24 publications

References 50 publications

Stromal cells downregulate miR-23a-5p to activate protective autophagy in acute myeloid leukemia

Stromal cells downregulate miR-23a-5p to activate protective autophagy in acute myeloid leukemia

Functions of the WNT Signaling Network in Shaping Host Responses to Infection

Method development and characterization of the low molecular weight peptidome of human wound fluids

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