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Use of Therapeutic Pathogen Recognition Receptor Ligands for Osteo-Immunomodulation.

ABSTRACT: Therapeutic pathogen recognition receptor (PRR) ligands are reaching clinical practice following their ability to skew the immune response in a specific direction. We investigated the effects of various therapeutic PRR ligands on bone cell differentiation and inflammation. Following stimulation, alkaline phosphatase (ALP) activity (Day 10), osteocalcin, osteonectin expression (Day 14), and calcium deposition (Day 21) were quantified in bone marrow-derived human mesenchymal stem cells (hMSCs). The osteoclastogenic response was determined by measuring tartrate-resistant acid phosphate (TRAP) activity in human monocytes. TNF-?, IL-6, IL-8, and IL-10 expressions were measured by enzyme-linked immunosorbent assay as an indicator of the ligands' inflammatory properties. We found that nucleic acid-based ligands Poly(I:C) and CpG ODN C increased early ALP activity in hMSCs by 4-fold without affecting osteoclast formation. These ligands did not enhance expression of the other, late osteogenic markers. MPLA, Curdlan, and Pam3CSK4 did not affect osteogenic differentiation, but inhibited TRAP activity in monocytes, which was associated with increased expression of all measured cytokines. Nucleic acid-based ligands are identified as the most promising osteo-immunomodulators, as they favor early osteogenic differentiation without inducing an exaggerated immune-cell mediated response or interfering in osteoclastogenesis and thus can be potentially harnessed for multifunctional coatings for bone biomaterials.

SUBMITTER: Khokhani P

PROVIDER: S-EPMC7957819 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Use of Therapeutic Pathogen Recognition Receptor Ligands for Osteo-Immunomodulation.

Khokhani Paree P Rahmani Nada R NR Kok Anne A Öner F Cumhur FC Alblas Jacqueline J Weinans Harrie H Kruyt Moyo C MC Croes Michiel M

Materials (Basel, Switzerland) 20210227 5

Therapeutic pathogen recognition receptor (PRR) ligands are reaching clinical practice following their ability to skew the immune response in a specific direction. We investigated the effects of various therapeutic PRR ligands on bone cell differentiation and inflammation. Following stimulation, alkaline phosphatase (ALP) activity (Day 10), osteocalcin, osteonectin expression (Day 14), and calcium deposition (Day 21) were quantified in bone marrow-derived human mesenchymal stem cells (hMSCs). Th ...[more]

PMID: 33673651

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Project description:Antigen presenting cells (APCs) regulate the balance of our immune response towards microbes. Whereas immunogenic APCs boost inflammation and activate lymphocytes, the highly plastic cells can switch into a tolerogenic/suppressive phenotype that dampens and resolves the response. Thereby the initially mediated inflammation seems to prime the switch of APCs while the strength of activation determines the grade of the suppressive phenotype. Recently we showed that pathogen recognition receptor-mediated pro-inflammatory cytokines reprogram differentiating human blood monocytes in vitro towards an immunosuppressive phenotype through prolonged activation of signal transducer and activator of transcription (STAT) 3. The TLR7/8 ligand R848 (Resiquimod) triggers the high release of cytokines from GMCSF/IL-4-treated monocytes. These cytokines subsequently upregulate T cell factors, such as Programmed death-ligand 1 (PD-L1) and Indolamin-2,3-Dioxygenase (IDO) suppressive through cytokine receptor-mediated STAT3 activation. Here we reveal an essential role for the micro-RNA (miR) hsa-miR99b/let-7e/miR125a cluster in stabilizing the suppresive phenotype of R848-stimulated APCs on different levels. On the one hand the miR cluster boosts R848-stimulated cytokine production through regulation of MAPkinase inhibitor Tribbles homolog 2 (TRIB2), thereby enhancing cytokine-stimulated activation of STAT3. One the other hand, the STAT3 inhibitor suppressor of cytokine signaling-1 (SOCS-1) is targeted by the miR cluster, stabilizing the STAT3-induced expression of immunosuppressive factors PD-L1 and IDO. Finally hsa-miR-125a/let7e/99b cluster regulates generation of the suppressive tryptophan (Trp) metabolite kynurenine by targeting the tryptophanyl -tRNA synthetase WARS, the direct competitor of IDO in terms of availability of Trp. In summary, our results reveal the hsa-miR99b/let-7e/miR125a cluster as an important player in the concerted combination of mechanisms that stabilizes STAT3 activity and thus regulate R848-stimulated suppressive APCs.

Dataset Information

Use of Therapeutic Pathogen Recognition Receptor Ligands for Osteo-Immunomodulation.

Publications

Use of Therapeutic Pathogen Recognition Receptor Ligands for Osteo-Immunomodulation.

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