CD56+ monocytes have a dysregulated cytokine response to lipopolysaccharide and accumulate in rheumatoid arthritis and immunosenescence

Abstract

IntroductionPeripheral blood monocytes are no longer regarded as a homogeneous cell population, but can be differentiated both phenotypically and functionally into various subpopulations. In rheumatoid arthritis, the subpopulation of CD14bright/CD16+ monocyte is expanded and prone towards generation of Th17 cells. CD56+ monocytes represent a different subpopulation, which is also expanded in conditions associated with autoimmunity like inflammatory bowel diseases. The aim of the study was the quantification and functional characterization of the CD56+ monocyte subset in rheumatoid arthritis (RA).MethodsFrequencies of peripheral blood monocyte subpopulations were analyzed by flow cytometry in 86 healthy controls and 75 RA patients. In 16 patients, anti-tumor necrosis factor (TNF) therapy was initiated, and the CD56+ monocyte frequency was monitored longitudinally. Lipopolysaccharide (LPS)-induced cytokine production of CD56+ and CD56– monocytes was determined by intracellular staining or cytokine secretion assays.ResultsIn healthy individuals, 8.6% ± 0.6 of the monocytes co-expressed CD56, with the majority of CD56+ monocytes being CD14bright (7.9% ± 0.5), while only a minor population was CD14dim (0.7% ± 0.1). We found a strong positive correlation between an individual’s age and the frequency of CD56+ monocytes. Upon stimulation with LPS, CD56+ monocytes became more frequently positive for TNF, IL-10 and IL-23 than CD56– monocytes. In addition, CD56+ monocytes spontaneously produced more reactive oxygen intermediates than CD56- monocytes. In RA patients, the frequency of CD56+ monocytes was significantly higher than in healthy controls (12.2% ± 0.9 vs. 7.9% ± 0.5, p = 0.0002), and this difference most pronounced in RA patients below 40 years of age (11.1% ± 1.6 vs. 4.1% ± 0.4, P < 0.0001). Treatment of the patients with an anti-TNF blocking agent significantly reduced CD56+ monocyte frequencies (baseline 12.4% vs. 24 weeks treatment 8.0%, P = 0.0429), and the magnitude of this decrease was found to correlate with the change in disease activity under the therapy.ConclusionThe CD14bright/CD56+ monocyte subset is expanded in aging individuals as well as in patients with RA. The pro-inflammatory production of cytokines and reactive oxygen species as well as the elimination of those cells in patients with a good response towards TNF inhibiting agents indicates a possible contribution of those monocytes in the inflammatory response in RA.

Bullous pemphigoid outcome is associated with CXCL10-induced matrix metalloproteinase 9 secretion from monocytes and neutrophils but not lymphocytes

“…In this line it was shown that CD14 1 CD56 1 monocytes also expressing CD16 were more prone to express inflammatory cytokines, such as IL-1b and IL-23, and were expanded in conditions associated with inflammatory and autoimmune diseases. [39][40][41] Although this monocyte subset still need to be investigated in patients with BP, one can notice that IL-23 is overexpressed in the serum of patients with BP compared with expression in age-and sexmatched control subjects and is even increased in the serum of patients with BP who later experience a relapse. 6 Because CXCL10 increases its own production by monocytes in some patients with BP, this could further amplify MMP-9 production in those patients.…”

The current relevance and use of prednisone in rheumatoid arthritis

“…This assumption is emphasized by the recent findings about reverse signaling through the transmembrane TNF (tmTNF): we were able to show that infliximab ligation of tmTNF on monocytes leads to inhibition of the constitutive NF-kB activation, suppresses spontaneous IL-1b production and induces apoptosis within monocytes in RA patients but not in healthy controls [7]. There is also evidence that the monocyte cell set in RA is disturbed with patients having expanded pathological subsets at the expense of classical monocytes [8,9]. This paper is not aiming to deliver a detailed description of the assumed pathogenic process leading to RA though.…”

Macrophage Functional Disorders in Rheumatoid Arthritis and Atherosclerosis

“…Кроме того, М1-макрофаги могут дифференцироваться в остеокласты и участвовать в образовании костных эрозий при РА [53]. Важная роль в поддержании хронического ревматоидного воспаления отводится М1-макрофагам, продуцирующим основные «провоспалительные» цитокины (ФНОα, ИЛ1, ИЛ6, ИЛ12 и ИЛ23) [54]. Установлено, что у больных РА уровни активности и экспрессии ИЛ23 сыворотки и сиртуина 1 (sirtuins, или Silent Information Regulator 1 proteins -SIR1) нарушались параллельно увеличению апоптоза мононуклеарных клеток периферической крови [55].…”