Circulating and Synovial Monocytes in Arthritis and Ex-Vivo Model to Evaluate Therapeutic Modulation of Synovial Monocytes

Figures & data

Figure 1. Therapeutics in arthritis management detailed in this review and their route of administration.

Figure 2. Distribution and main characteristics of circulating and synovial monocyte subsets in joint inflammation. (a) Prevalence (%) of monocytes among total leukocytes and monocytes subsets according to CD14 and CD16 expression (b) Monocytes from the circulation migrate to the synovium and lead to imbalance of M1/M2 macrophages responsible for inflammation. CCL2 influx leads to monocyte migration from the circulation to the joints. As a consequence, M1 macrophages producing the pro-inflammatory cytokines IL-1β, IL-6, and TNF are up-regulated, while the anti-inflammatory M2 macrophages producing TGF-β and IL-10 are down-regulated. This event promotes synovial tissue damage instead of tissue repair. Abbreviations: Chemokine (C-C motif) ligand 2 (CCL2) cluster differentiation (CD), interleukin (IL), macrophage (M) transforming growth factor-beta (TGF-β) and tumor necrosis factor (TNF).

Table 1. Effect of therapeutic agents on monocyte populations.

Drug class	Peripheral monocytes	Synovial monocytes	Citation
GCs	Unchanged	Unchanged	Peripheral: Liu et al. (2015)
			Synovial: Makrygiannakis et al. (2008)
MTX	↓	↓ dose-dependent	Peripheral: Chara et al. (2015)
			Synovial: Cutolo et al. (2000)
Hydroxychloroquine	Unknown (reduce cytokine production by monocytes)	Unknown	Peripheral: Muller-Calleja et al. (2017)
Leflunomide	Unknown	↓	Synovial: Cutolo et al. (2003)
TNFi	↓	↓	Peripheral: Batko et al. (2019) and Huang et al. (2018)
			Synovial: Gertel et al. (2023) and Taylor et al. (2000)
IL-6 receptor inhibitors	↓	Unchanged	Peripheral: Tsukamoto et al. (2018)
			Synovial: Chatzidionysiou et al. (2021)
CD-20 inhibitors	Overall anti-inflammatory benefit	↓	Peripheral: Toubi et al. (2007) Synovial: Thurlings et al. (2008)
CTLA-4 Ig	Overall anti-inflammatory benefit	Unknown	Peripheral: Cutolo et al. (2021)
IL-17A inhibitors	Unknown	↓	Synovial: Shahrara et al. (2009)
IL-12/23 inhibitors	Unknown	↓	Synovial: Fiechter et al. (2021)
JAK Inhibitors	↓	↓	Peripheral and Synovial: Yarilina et al. (2012)
GM-CSF inhibitors	Unknown	↓	Synovial: Greven et al. (2015)
CCR2/CCR5 dual inhibitor (cenicriviroc)	Unknown	↓	Synovial: Mondadori et al. (2021)
Mesenchymal Stem Cells (MSCs)	Unknown Overall anti-inflammatory benefit	Unknown	Peripheral: Mancuso et al. (2019)
Platelet Rich Plasma (PRP)	Unknown Increase M2/M1 macrophages ratio	Unknown	Peripheral: Uchiyama et al. (2021)

Figure 3. Schematic overview of ex-vivo system to analyze drugs effect on SFMCs derived from arthritis patients. The synovial cells are extracted and cultured ex-vivo with the drugs of interest. The activity of the drugs is then compared to control drugs with known mechanisms of action currently in use to treat joint disease (e.g., GCs: methylprednisolone (MPA) and betamethasone (BET)). Next, the cells are analyzed for changes of surface markers by flow cytometry, cytokine secretion, and gene expression. The effect of each drug on monocyte populations is then determined. This ex-vivo system could be used for analyzing the potential utilization of therapeutic agents for the treatment of different inflammatory arthritis types.

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