Background and objectivesThe IL-36 family of cytokines comprises three agonists: IL-36α, IL-36β and IL-36γ, an antagonist: IL-36Ra, and IL-38: another potential IL-36 inhibitor. IL-36 agonists are highly expressed in skin and are involved in the pathogenesis of psoriasis, while antagonists limit uncontrolled inflammation. The expression and role of IL-36 cytokines in other chronic inflammatory diseases is currently debated. In this study, we compared the expression profile of IL-36 cytokines in psoriasis, RA and CD.Materials and methodsSkin, joint and colon inflammation was induced in mice. Skin, synovial and colonic biopsies from patients respectively with psoriasis, RA or CD were collected. Synovial fluids from patients with RA were also collected. These samples were analysed for cytokines expression by RT-qPCR, ELISA, immunohistochemistry and confocal microscopy. The cell sources of IL-36 cytokines were confirmed in cell cultures after stimulation with inflammatory cytokines and TLR agonists by RT-qPCR.ResultsDuring imiquimod-induced mouse skin inflammation and in human psoriasis, expression of IL-36α, γ and IL-36Ra, but not IL-36β and IL-38, was induced and correlated with Th17 cytokines (IL-17A, IL-22…). In mice with collagen-induced arthritis and in the synovium of patients with RA, IL-36α, β, γ, IL-36Ra and IL-38 were all elevated and correlated with myeloid cytokines such as CCL3, CCL4 and MCSF, but not with Th17 cytokines. In mice with dextran sulfate sodium-induced colitis and in patients with CD, only IL-36α, γ and IL-38 were induced at a relatively low level. Only a minor subgroup of patients with RA (17–29%) or CD (25%) had an elevated IL-36 agonists/antagonists ratio, versus 93% of patients with psoriasis. By IHC and in cell cultures, the different IL-36 cytokines were produced at different levels by human keratinocytes, CD68+ inflammatory macrophages, dendritic/Langerhans cells, and CD79α+ plasmocytes.ConclusionExpression of the different IL-36 cytokines is differently regulated and their cell sources are distinct. This helps to explain the different expression profiles observed in three chronic inflammatory diseases and why only a minor subgroup of RA and CD patients have an elevated IL-36 agonists/antagonists ratio. Additional studies are necessary to better identify these patients and to investigate whether they would benefit from IL-36 neutralisation.

BACKGROUND: Epidemiological, imaging, and anatomical studies suggest an association between proximal arterial atherosclerosis and development of low back pain (LBP). OBJECTIVES: We aimed to define (1) the frequency and (2) factors associated with exercise-induced proximal ischemia (EIPI) in individuals with LBP and (3) develop a clinical screening scale. DESIGN: Monocentric cross-sectional study. PARTICIPANTS: All patients with history of ongoing LBP referred to our exercise investigation laboratory for exercise transcutaneous oximetry (ex-tcPO 2 ) between January 2011 and December 2017 (n = 542; mean age, 65.4 ± 10.9; 83.9% men). MAIN MEASURES: EIPI was defined as a decrease from rest of oxygen pressure (DROP) below − 15 mmHg on the lumbar and/or buttock probes. Ex-tcPO 2 is a reliable validated tool for diagnosing EIPI in comparison with arteriography and computed tomography angiography. Ex-tcPO 2 was performed on a treadmill until symptom manifestation or exhaustion. Clinical data were collected using interview questionnaires, medical file review, and clinical examination. KEY RESULTS: EIPI was diagnosed in 282 patients (52%). Age ≤ 70 years (OR, 2.22; 95% CI, 1.35-3.57; p = 0.002), a history of proximal revascularization (OR, 2.64; 95% CI, 1.50-4.65; p = 0.001), use of antiplatelet medication (OR, 1.71; 95% CI, 0.96-3.06; p = 0.069), a relationship between exercise and LBP (OR, 2.61; 95% CI, 1.49-4.57; p = 0.001), and an abnormal ankle to brachial index (OR, 2.87; 95% CI, 1.77-4.66; p < 0.0001) were identified as EIPI predictors. Using these items, we developed a screening scale that showed an area under the receiver operating characteristics curve of .756. At a score of ≥ 3, the sensitivity, specificity, and accuracy for EIPI were 84%, 55%, and 71%, respectively. CONCLUSIONS: EIPI was common among our patients with LBP undergoing ex-TcPO 2 . Our screening scale could help better select the patients who require angiography.

BackgroundMacrophages play a major role in the pathogenesis of rheumatoid arthritis (RA). There are professional phagocytic cells present in all organs to maintain tissue integrity, clear debris, and respond rapidly to initiate repair after injury. These cells can produce inflammatory cytokine such as TNF α. They can differentiate into two sub-populations: the proinflammatory M1 and anti-inflammatory M2 macrophages. It has been suggested that chronic inflammation could be enhanced by an imbalance between these two subpopulations with and excess of M1 over M2 polarization.ObjectivesThe goal of our work was to study the kinetic and pattern of infiltration of these cells in the synovial tissue during the course of arthritis.MethodsWe used a murine animal model of antigen-induced arthritis (AIA), which is characterized by an acute arthritis followed by a spontaneous resolution of inflammation over time. Sixteen C57BL/6 mice aged 7 weeks were used.They were sacrificed at various clinical stages of arthritis: early (D3), peak (D7), stabilization (D10) and decline (D14). Expression of M1 and M2 markers within the joint was studied by RT-qPCR using the following markers: CD11b (myeloid cells), CD64 and CD86 (M1), CD163, IL-10 and CD200R (M2). The different macrophage subtypes were studied by immunohistochemistry (IHC) using the following markers: Iba-1 (pan-macrophage or M0), iNOS (M1), CD206 (M2). Finally, human synovial samples from RA patients (n=19) were using the following markers: CD68 (M0), iNOS (M1), CD163 (M2).ResultsIn the AIA model, the expression of CD11b was significantly increased over time. M1 markers expression was significantly increased early, on D3 (4 and 7 times for CD86 and CD64, respectively) then slowly decreased without returning to baseline (2.5 and 4 times on day 14 for CD86 and CD64, respectively; p≤0.05). Expression of the M2 markers (IL-10, CD200r1 and CD163) was modulated differently. CD163 marker decreased by 5 times at D3 (p=0.05), and quickly returned to its basal expression. The IL-10 marker increased more gradually with maximum expression of 5.5 times on D7 (p≤0.05). Finally, the marker CD200r1 increased in the early phase D3 (p≤0.05), stabilized and then decreased in decline D14. On IHC, INOS staining (M1) was maximal on D7 (score 10, p≤0.05) and decreased over time. The CD206 marking (M2) increased progressively to its maximum on D14 (score 7; p≤0.05). In human synovial biopsies intensity iNOS marking (M1) but not CD163 (M2) was correlated with the histological inflammation (p=0.0091; r =0.5806). In contrast, presence of M2 macrophages was associated with fibrinoid necrosis (p=0.002 and correlation coefficient r =0.7606).ConclusionsWe did not find any real switch M1/M2 over time but a “cohabitation” of these two macrophages sub-types. However, an earlier increase in the M1 population and an inversion of the ratio M1/M2 in the resolution phase of arthritis as been observed in the AIA model. In human synovial tissues the correlation between the fibrinoid necrosis and the presence of subp...