Targeting CD1c-expressing classical dendritic cells to prevent thymus and activation-regulated chemokine (TARC)-mediated T-cell chemotaxis in rheumatoid arthritis

Abstract

Objectives: Thymus and activation-regulated chemokine (TARC) attracts cells that express the C-C chemokine receptor type 4 (CCR4), including CD4 T cells. As expression of CCR4 is increased on peripheral T cells and intraarticular interleukin (IL)-17-producing cells in patients with rheumatoid arthritis (RA), we investigated whether TARC plays a role in the attraction of T cells to the synovial compartment. In addition, we assessed the role of classical dendritic cells (cDCs) in the production of TARC in RA. Method: TARC was measured in synovial fluid (SF) samples from RA and osteoarthritis (OA) patients. Spontaneous and thymic stromal lymphopoietin (TSLP)-induced TARC production by mononuclear cells (MCs) and CD1c cDCs from peripheral blood (PB) and SF was assessed. The role of TARC in CD4 T-cell migration towards cDCs was assessed and the contribution of CD1c-expressing cells to TARC production was studied. Results: TARC concentrations were higher in SF of RA patients compared to OA patients. MCs from SF produced TARC spontaneously and produced more TARC upon stimulation than paired PBMCs. Blocking TARC strongly inhibited CD4 T-cell chemotaxis by TSLP-stimulated cDCs, associated with decreased production of tumour necrosis factor (TNF)-α. Depletion of cDCs from SFMCs strongly reduced TARC production. Conclusions: TARC levels are increased in RA SF and our data indicate that this results from production by SFMCs and in particular CD1c cDCs. TARC attracts T cells and TARC secretion by MCs is crucially dependent on the presence of CD1c cDCs. Considering the potential of SF cDCs to activate T cells and induce proinflammatory cytokine secretion, targeting intra-articular cDCs constitutes a novel therapeutic approach in RA.

CCL17 blockade as a therapy for osteoarthritis pain and disease

“…CCL17 was originally considered to be a M2 cytokine due to its preferential attraction of T H 2 lymphocytes [25,40]. It can be produced by certain macrophage/dendritic cell populations [18,23,41,42] and is elevated in many inflammatory conditions [18,[43][44][45] and in synovial fluid in OA [46]. CiOA synovitis in the absence of CCL17 suggests that CCL17 has other functions, apart from a chemotactic role [18].…”

“…As mentioned, lowgrade inflammation is now being recognized as important in OA pathogenesis and progression [2-6, 33, 66] and pain has the highest impact on its burden [65]. Targeting GM-CSF or its receptor in RA is yielding promising results [15] and, as a result of prior findings in the CiOA model [8], a phase II trial in hand OA is currently underway [15]; however, given the possible adverse side effects associated with GM-CSF/GM-CSFR blockade, such as pulmonary alveolar proteinosis and infections [16,67], targeting CCL17, which is elevated in the synovial fluid of patients with OA [46] and which we have found to be downstream of GM-CSF [18], may have some advantages for the treatment of not only inflammatory arthritis but also at least for some patients with OA.…”

CCL17 blockade as a therapy for osteoarthritis pain and disease

“…CCL17 was originally considered to be a M2 cytokine due to its preferential attraction of T H 2 lymphocytes [ 25 , 40 ]. It can be produced by certain macrophage/dendritic cell populations [ 18 , 23 , 41 , 42 ] and is elevated in many inflammatory conditions [ 18 , 43 – 45 ] and in synovial fluid in OA [ 46 ]. CiOA synovitis in the absence of CCL17 suggests that CCL17 has other functions, apart from a chemotactic role [ 18 ].…”

“…As mentioned, low-grade inflammation is now being recognized as important in OA pathogenesis and progression [ 2 – 6 , 33 , 66 ] and pain has the highest impact on its burden [ 65 ]. Targeting GM-CSF or its receptor in RA is yielding promising results [ 15 ] and, as a result of prior findings in the CiOA model [ 8 ], a phase II trial in hand OA is currently underway [ 15 ]; however, given the possible adverse side effects associated with GM-CSF/GM-CSFR blockade, such as pulmonary alveolar proteinosis and infections [ 16 , 67 ], targeting CCL17, which is elevated in the synovial fluid of patients with OA [ 46 ] and which we have found to be downstream of GM-CSF [ 18 ], may have some advantages for the treatment of not only inflammatory arthritis but also at least for some patients with OA.…”

Chemokines and chemokine receptors as promising targets in rheumatoid arthritis

“…Peripheral blood mononuclear cells (PBMCs) derived from patients with RA highly express CCL2, CCL3, CXCL2, and CX 3 CL1 compared to those derived from HD ( 91 – 93 ). These chemokines are differentially produced by different immune cells in patients with RA: T cells produce CCL3, CCL4, CCL5, and CXCL13 ( 93 – 96 ); B cells express CXCL9/10 ( 97 ); monocytes generate CCL2, CCL18, CCL19, and CX 3 CL1 ( 93 , 98 , 99 ); macrophages express CCL25, CXCL4, CXCL7, and CX 3 CL1 ( 93 , 100 , 101 ); dendritic cells (DCs) produce CCL17, CCL18, and CCL19 ( 102 – 104 ); and neutrophils generate CCL3 and CCL18 ( 103 , 105 , 106 ).…”