Shaping of Monocyte-Derived Dendritic Cell Development and Function by Environmental Factors in Rheumatoid Arthritis

Abstract

Dendritic cells (DC) are heterogeneous cell populations essential for both inducing immunity and maintaining immune tolerance. Chronic inflammatory contexts, such as found in rheumatoid arthritis (RA), severely affect the distribution and the function of DC, contributing to defective tolerance and fueling inflammation. In RA, the synovial fluid of patients is enriched by a subset of DC that derive from monocytes (Mo-DC), which promote deleterious Th17 responses. The characterization of environmental factors in the joint that impact on the development and the fate of human Mo-DC is therefore of great importance in RA. When monocytes leave the blood and infiltrate inflamed synovial tissues, the process of differentiation into Mo-DC can be influenced by interactions with soluble factors such as cytokines, local acidosis and dysregulated synoviocytes. Other molecular factors, such as the citrullination process, can also enhance osteoclast differentiation from Mo-DC, favoring bone damages in RA. Conversely, biotherapies used to control inflammation in RA, modulate also the process of monocyte differentiation into DC. The identification of the environmental mediators that control the differentiation of Mo-DC, as well as the underlying molecular signaling pathways, could constitute a major breakthrough for the development of new therapies in RA.

Distinct cross talk of IL‐17 & TGF‐β with the immature CD11c+TRAF6(−/−)‐null myeloid dendritic cell‐derived osteoclast precursor (mDDOCp) may engage signaling toward an alternative pathway of osteoclastogenesis for arthritic bone loss in vivo

“…These data strongly suggested that myeloid CD11c + DCs were closely associated with the presence of double‐positive CD11c + TRAP + TRAF6 (−/−) DC‐like OCs physically located in both inflamed tissues and eroded bone surfaces of CC‐II‐immunized T6KO_bmChi‐DC mice, lacking the Mo/Mϕ‐derived classical OCs in vivo (Figure 3 legend). Meanwhile, some significant numbers of TRAP (+) CD11c (−) ‐“single‐positive” cells were detected mainly in hind limbs’/joints’ tissue sites ( p = .015) rather than those in bone surfaces of the T6KO_bmChi‐CC‐II mice, suggesting that some synovial associated tissue‐bound Mo/Mϕ subset(s) may have been activated under inflammatory environments in situ, consistent with the well‐described phenomenon reported in the past 13,18,19,38–40,43–45 …”

“…Through the dual IHC and quantification of specific DCs subsets studied, the present findings clearly provided the direct physical evidence that CD11c + TRAP + mDCs‐OCp/DC‐like OCs were significantly involved in driving an alternative pathway for inflammation‐induced osteoclastogenesis in vivo, without the Mo/Mϕ‐derived classical OCs in CC‐II‐immunized TRAF6 (−/−) ‐null chimeras. Meanwhile, IL‐17/IL‐17Rs signaling engages distinctive interplays with CD11c + TRAP + TRAF6 (−/−) DC‐like OCs via TGF‐β‐mediated “stepwise” development for subsequent osteoclastogensis and arthritic bone loss, without TRAF6‐mediated signaling or/and intermediates in vivo, which is an uniquely new finding that has not been revealed previously 5,9,13,14,33,38–47 . Interestingly, the dual IHC stained CD11c + TRAP + DC‐like OCs represented the majority of infiltrating immune cells physically detected in the inflamed synovium/bone surfaces of hind limbs of the CC‐II‐immunized WT‐mice, quantitatively indifferent to those TRAP (+) CD11c (−) ‐single‐positive cells (i.e., representing CD11c (−) Mo/Mϕ‐derived TRAP + OCs) in the tissue counterparts (Figure 2; p > .05), which was sought traditionally as the dominant cell types responsibly attributed to inflammatory bone loss/resorption.…”

Impact of the host response and osteoblast lineage cells on periodontal disease

“…Osteoclasts originate from cells of the mononuclear phagocyte lineage and are responsible for bone resorption ( 23 ). Osteoclast precursors can be formed from immature monocytic cells, immature monocyte-derived dendritic cells and resident macrophages ( 24 , 25 ). Osteoclast precursors are recruited to sites of inflammation by chemokines such as CCL2, CXCL16, and CX3CL1.…”

NR4A1-3 nuclear receptor activity and immune cell dysregulation in rheumatic diseases

“…IMRDs are a heterogeneous group of diseases and display differences in genetic susceptibility loci, immune system activation, environmental risk factors and treatment response patterns (6)(7)(8). Recent approaches to further understand the pathogenic mechanisms of IMRDs, combined with molecular analysis of disease response following targeted cytokine therapy, are providing critical molecular characterization and mechanistic knowledge of the shared pathophysiology and differences that exist across IMRDs (1).…”