TY - JOUR
T1 - MAPK activated kinase 2 inhibition shifts the chemokine signature in arthritis synovial fluid mononuclear cells from CXCR3 to CXCR2
AU - Kragstrup, Tue W
AU - Sørensen, Anne Sofie
AU - Brüner, Mads
AU - Lomholt, Søren
AU - Nielsen, Morten A
AU - Schafer, Peter
AU - Deleuran, Bent
N1 - Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.
PY - 2022/11
Y1 - 2022/11
N2 - Background: The development of novel treatment strategies of immune-mediated inflammatory arthritis (IMIA) is still a clinical unmet need. The mitogen-activated protein kinase (MAPK) pathway is activated by environmental stressors, growth factors and inflammatory cytokines. However, the inhibition of central MAPK proteins has so far had undesirable side effects. The MAPK-activated protein kinase 2 (MK2) is a downstream mediator in the MAPK signaling pathway. Objectives: The objective of this study was to explore the effects of a small molecule inhibiting MK2 on synovial fluid mononuclear cells from patients with IMIA. Methods: Synovial fluid mononuclear cells (SFMCs) were obtained from a study population consisting of patients with active rheumatoid arthritis (RA), peripheral spondyloarthritis (SpA) or psoriatic arthritis (PsA) with at least one swollen joint (for obtaining synovial fluid) (n = 11). SFMCs were cultured for 48 h with and without the MK2 inhibitor CC0786512 at 1000 nM, 333 nM and 111 nM and cell free supernatants were harvested and frozen before they were analyzed by the Olink proseek multiplex interferon panel. Results: In SFMCs cultured for 48 h, the MK2 inhibitor decreased the production of chemokine (C-X-C motif) ligand 9 (CXCL9) (P < 0.001), CXCL10 (P < 0.01), hepatocyte growth factor (HGF) (P < 0.01), CXCL11 (P < 0.01), tumor necrosis factor-like weak inducer of apoptosis (TWEAK) (P < 0.05), and interleukin 12B (IL-12B) (P < 0.05) and increased the production of CXCL5 (P < 0.0001), CXCL1 (P < 0.0001), CXCL6 (P < 0.001), transforming growth factor alpha (TGFα) (P = 0.01), monocyte-chemotactic protein 3 (MCP-3) (P < 0.01), latency-associated peptide (LAP) TGFβ (P < 0.05) dose-dependently. Conclusions: This study reveals the downstream effects of MK2 inhibition on the secretory profile of SFMCs. Specifically, C-X-C motif chemokine receptors 3 (CXCR3) chemokines were decreased and CXCR2 chemokines were increased. This shift in the chemokine milieu may be one of the mechanisms behind the anti-inflammatory effects of MK2 inhibitors.
AB - Background: The development of novel treatment strategies of immune-mediated inflammatory arthritis (IMIA) is still a clinical unmet need. The mitogen-activated protein kinase (MAPK) pathway is activated by environmental stressors, growth factors and inflammatory cytokines. However, the inhibition of central MAPK proteins has so far had undesirable side effects. The MAPK-activated protein kinase 2 (MK2) is a downstream mediator in the MAPK signaling pathway. Objectives: The objective of this study was to explore the effects of a small molecule inhibiting MK2 on synovial fluid mononuclear cells from patients with IMIA. Methods: Synovial fluid mononuclear cells (SFMCs) were obtained from a study population consisting of patients with active rheumatoid arthritis (RA), peripheral spondyloarthritis (SpA) or psoriatic arthritis (PsA) with at least one swollen joint (for obtaining synovial fluid) (n = 11). SFMCs were cultured for 48 h with and without the MK2 inhibitor CC0786512 at 1000 nM, 333 nM and 111 nM and cell free supernatants were harvested and frozen before they were analyzed by the Olink proseek multiplex interferon panel. Results: In SFMCs cultured for 48 h, the MK2 inhibitor decreased the production of chemokine (C-X-C motif) ligand 9 (CXCL9) (P < 0.001), CXCL10 (P < 0.01), hepatocyte growth factor (HGF) (P < 0.01), CXCL11 (P < 0.01), tumor necrosis factor-like weak inducer of apoptosis (TWEAK) (P < 0.05), and interleukin 12B (IL-12B) (P < 0.05) and increased the production of CXCL5 (P < 0.0001), CXCL1 (P < 0.0001), CXCL6 (P < 0.001), transforming growth factor alpha (TGFα) (P = 0.01), monocyte-chemotactic protein 3 (MCP-3) (P < 0.01), latency-associated peptide (LAP) TGFβ (P < 0.05) dose-dependently. Conclusions: This study reveals the downstream effects of MK2 inhibition on the secretory profile of SFMCs. Specifically, C-X-C motif chemokine receptors 3 (CXCR3) chemokines were decreased and CXCR2 chemokines were increased. This shift in the chemokine milieu may be one of the mechanisms behind the anti-inflammatory effects of MK2 inhibitors.
KW - Kinase
KW - Rheumatoid arthritis
KW - Small molecules
KW - Immune-mediated inflammatory arthritis
KW - Spondyloarthritis
KW - Psoriatic arthritis
KW - Receptors, Interleukin-8B/metabolism
KW - Synovial Fluid/chemistry
KW - Transforming Growth Factor beta/metabolism
KW - Humans
KW - Cells, Cultured
KW - Hepatocyte Growth Factor/metabolism
KW - Chemokines/metabolism
KW - Arthritis, Psoriatic/drug therapy
KW - Interleukin-12 Subunit p40/metabolism
KW - Transforming Growth Factor alpha/analysis
KW - Mitogen-Activated Protein Kinases/metabolism
KW - Ligands
KW - Synovial Membrane/metabolism
KW - Interferons/metabolism
KW - Anti-Inflammatory Agents/metabolism
U2 - 10.1016/j.intimp.2022.109267
DO - 10.1016/j.intimp.2022.109267
M3 - Journal article
C2 - 36179420
SN - 1567-5769
VL - 112
JO - International Immunopharmacology
JF - International Immunopharmacology
M1 - 109267
ER -