Tofacitinib, a small molecule JAK inhibitor, was recently shown to reduce disease flares and improve disease activity and physical function in patients with polyarticular JIA [152]. and M activation is usually involved in JIA pathogenesis and focus on the signaling pathways and mechanisms participating in the related cell activation processes. and investigated the distribution of Mo subsets in paired SF and blood samples from patients with oligoarticular JIA and ERA. These authors discovered that while classical CD14++CD16? Mos dominate in the blood circulation, intermediate CD14++CD16+ Mos were highly enriched in oligoarticular JIA and ERA patient SF [28,29,30]. As CD14++CD16+ synovial Mos can be induced by cytokine-rich SF and are found with comparable patterns across Mo subsets, reports have suggested that this increased CD16 expression in these cells may likely result from the cytokine milieu of the synovial space and not the recruitment of intermediate CD14++CD16+ Mos from blood circulation due to their unique features [28,31]. Specifically, cytokines, such as IL-10 and transforming growth factor beta ML418 (TGF), in SF are potent inducers of CD16, an activating Fc receptor (FcR), expression in Mos [28,29]. As exhibited by et al., the Mo lineage is usually expanded in patients with active sJIA ML418 [30,32]. While increased levels of CD14 and CD16 were found on sJIA Mos in both the flare and quiescence status, the distribution of the CD14+CD16+ Mo subsets was not altered compared to that in healthy controls [30,32]. Both classical CD14++CD16- Mos and CD14+CD16+ Mos are activated in sJIA [30]. The increased expression RHOH12 of CD14, a pattern acknowledgement receptor that binds lipopolysaccharide (LPS) and other microbial molecules, on sJIA Mos was proposed by et al. to contribute to the apoptosis resistance of Mos [33]. Seemingly important players in JIA, intermediate Mos are noted for their high surface levels of class II molecules, CD40, CD54, and CD74, which are capable of inducing T cell activation and proliferation [34,35]. Upon encountering damage-associated molecular patterns or pathogen-associated molecular patterns, such as LPS, these Mos preferentially produce IL-1, IL-6, ML418 and tumor necrosis factor (TNF) [36,37]. Furthermore, in response to vascular endothelial growth factor (VEGF), CD14+CD16+ Mos form cell clusters and exhibit proangiogenic behavior [38]. In a rheumatoid arthritis (RA) study, a coculture of intermediate CD14++CD16+ Mos from arthritis patients with na?ve T cells skewed the T cells toward pathogenic Th17 cells via the production of IL-23. The increased frequency of IL-17-generating natural killer (NK) cells, ML418 CD4, and gamma-delta T cells in patients with ERA was also recently proposed to result from the growth of intermediate CD14++CD16+ Mos due to their role as the major producer of IL-23, a key cytokine in the pathogenesis of ERA [26]. 3.2. Monocyte/Macrophage Polarization Plasticity and heterogenicity are the hallmarks of Mos/Ms. Polarization is believed to influence disease progression by altering effector function [37] and has been linked to osteoclastogenesis in RA, to disease severity in osteoarthritis, and to unique JIA subtypes [29,34,39,40,41]. Demonstrated by the acquisition of unique functional characteristics directed by the immunological microenvironment and tissue milieu, polarized Mos/Ms are referred to as classically activated (M1) or alternatively activated (M2) Ms, mirroring the Th1/Th2 nomenclature [42]. Based on the induction of cytokines and clinical features involving tissue repair, angiogenesis, and immune regulation, alternatively activated Ms have been further subcategorized [39,43] (Table 1). Table 1 Characteristics of monocyte and macrophage polarization in humans. et al. suggested that this inflammatory features of those who suffered from oligoarticular JIA may not fit into the traditional dichotomous polarization groups and should be considered according to their unique pattern [31]. Specifically, compared to circulating Mos, the synovial Mos were polarized with a mixed classically and alternatively activated pattern. This was evidenced by the increased expression of the surface molecules CD40, CD86, and CD206 and by mRNA.