Background/Purpose: Inflammation is part of the complex biological response of body tissues to harmful stimuli, involving immune cells, blood vessels, and molecular mediators. At the initial phase, characterized by an increase in pro-inflammatory cytokines aiming to neutralize the tissue injury, the resolution process must follow to down-regulate the inflammation and to promote tissue repair. That latter phase is driven by the so called Specialized Pro-Resolving Mediators (SPMs), such as Resolvin (RvD and RvE), Protectins, Maresins and Lipoxin A4 (LXA4), bioactive metabolites of omega-3 fatty acids that act by interacting with specific cellular receptors: CMKLR1, FPR2 and GPR32. In rheumatoid arthritis (RA) the reactive inflammation becomes persistent and the innate immune response turns into the adaptive immune activation. Nowadays there is no evidence whether SPMs are involved in RA pathogenesis. Purpose of this study was to evaluate the expression of CMKLR1, FPR2 and BLT1 in RA patients and to correlate it to the disease activity.

Methods: Patients affected with RA, according to the 2010 EULAR/ACR classification criteria, were enrolled in this study. Exclusion criteria were: minority age, status of pregnancy or breastfeeding, concomitant any other autoimmune disease. At entry, ESR, CRP, DAS28-ESR, CDAI, Health Assessment Questionnaire Disability Index (HAQ) and peripheral venous blood sample were collected. Based on DAS28-ESR, patients were divided into high-moderate (H-Mo/RA if DAS28-ESR ≥ 3.2) and low-remission (L-Rem/RA if DAS28 < 3.2) disease activity group. The expression of CMKLR1, FPR2 and BLT1 in peripheral T cells (CD3) and B cells (CD19), monocytes (CD14) and granulocytes (gated by high side scatter), was evaluated by flow-cytometry assay. Differences for continuous variables were evaluated using the Mann-Whitney test, while for categorical data the Fisher’s probability test. Correlations were assessed using the Spearman test.

Results: Thirty RA patients, 21 H-Mo/RA and 9 L-Rem/RA, and 6 healthy control (HC) were studied. While no difference in the expression of CMKLR1, FPR2 and BLT1 in RA vs HC was found, SPMs receptors were differently expressed on CD14-monocytes: BLT1⁺CD14⁺ cells were significantly higher in L-Rem/RA (90,96%) than in H-Mo/RA /RA (56,70%) (p: 0.0001). Likewise, FPR2⁺CD14⁺ cells were significantly higher in L-Rem/RA (92,29%) than in H-Mo/RA /RA (79,94%) (p: 0.01). We also demonstrated an inverse correlation between BLT1 level in monocytes and ESR (p: 0.01), CRP levels (p: 0.008), DAS28-ESR (p: 0.03), CDAI (p: 0,0076) and HAQ (p: 0,0138) and a weak correlation between FPR2 expression and HAQ (p: 0.05).

Conclusion: In this study, FPR2 and BLT1 expression seem to be regulated by the activity of RA disease. As FPR2 and BLT1 should be involved in down-regulating inflammation by monocytes, it might be hypothesized that a defective signalling through these SPMs receptors may contribute to prevent the beginning of resolution phase, perpetuating chronic inflammation in active RA. However, further studies are needed to explore the intrigue mechanisms beyond inflammation and its resolution.

« Back to 2018 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/identification-of-biomarkers-involved-in-the-resolution-phase-of-inflammation-specialized-pro-resolving-mediator-receptors-expression-in-rheumatoid-arthritis/