Career situation of first and presenting authorYoung investigator.IntroductionCCL17 and CCL22 are chemokines that bind to the receptor CCR4, which is expressed on various immune cells as well as on neurons. CCL17 has been shown to mediate the pro-inflammatory and algesic actions of GM-CSF in murine arthritis models1 and CCL22 could activate nociceptive neurons in cell culture2 or induce hyperthermia by acting on the hypothalamus.3 Our previous studies have indicated that chemokine production by osteoclasts (OCs) might contribute to bone damage and arthralgia in the presence of anti-citrullinated protein antibodies.4 5 ObjectivesWe analyzed the expression and potential roles of CCL17 and CCL22 during rheumatoid arthritis (RA).MethodsWe compared CCL17 and CCL22 levels in the sera of individuals at risk of developing RA, in patients at early stages of RA and in healthy controls. We also studied the production of these molecules in OC cultures. We analyzed whether CCL22 can induce arthralgia or affect OC development.ResultsSerum levels of CCL22 were elevated in individuals at risk of developing RA and in early untreated RA, when compared to healthy controls. On the contrary, CCL17 levels showed no significant difference between the studied cohorts. In the group of RA patients, higher CCL22 concentrations were associated with smoking. In OC cultures CCL22 production was triggered by M-CSF or GM-CSF and CCL22 levels correlated with both of these cytokines in the synovial fluid of RA patients. CCL22 induced arthralgia when injected into the ankle joints of mice and it stimulated OC differentiation in cell culture.ConclusionsThe early increase of CCL22 might contribute to the development of RA, potentially by inducing pain and osteoclastogenesis. Inflammatory cytokines, like GM-CSF and M-CSF, and also by environmental triggers such as smoking can contribute to the increase of CCL22.ReferencesAchuthan A, et al. J Clin Invest 2016.Oh SB, et al. J Neurosci 2001.Osborn O, et al. Cytokine 2011.Krishnamurthy A, et al. Ann Rheum Dis 2016.Wigerblad G, et al. Ann Rheum Dis 2016.Disclosure of InterestB. Réthi: None declared, A. Krishnamurthy: None declared, A. Circiumaru: None declared, K. Sakurabas: None declared, V. Joshua: None declared, M. Sun: None declared, C. Szu-Ying: None declared, M. Engström: None declared, H. Wähämaa: None declared, A. Hensvold: None declared, J. Smith Employee of: GSK, A. Catrina: None declared.
Allergic contact dermatitis (ACD) is a disease with few targeted therapies. Chemokines play an important role in ACD through the recruitment of T-cells that express the chemokine receptor (CKR) CXCR3. Chemokines signal through CKRs, a subgroup of the G proteincoupled receptor (GPCR) family, which are targeted in >30% of drugs. However, few drugs target CKRs. Classically, GPCRs were thought to act as simple switches turned on by agonists and off by antagonists. We now appreciate that GPCRs adopt multiple conformations that link to distinct signaling pathways, such as G-proteins and ß-arrestins (ßarrs). These pathways can be selectively activated by a novel class of receptor ligands, termed biased agonists, which signal through some pathways while blocking signaling through others. The purpose of this study was to determine the roles that G-proteins and ßarrs play in ACD by selectively targeting signaling with CXCR3 biased agonists. Mouse and human cell chemotaxis was determined through transwell migration, and the effects of CXCR3 ligands on ACD were assessed in the DNFB allergic contact hypersensitivity (CHS) mouse model. Patient biopsies of patch tested skin were analyzed. Our results show that ßarr signaling through CXCR3 is necessary for full efficacy chemotaxis of both mouse and human T-cells. A topically applied ßarr-biased ligand doubled (ph0.05) the CHS inflammatory response in WT, but not in ßarr2 KO or CXCR3 KO, mice. Flow cytometry of mouse skin demonstrated increased T-cells following ßarr-biased drug treatment. We conclude that CXCR3 ßarr-mediated signaling is critical for effector T-cell recruitment that underlies the inflammatory response in CHS. These findings suggest that biased ligands could be utilized to selectively target CKRs for therapeutic benefit.
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