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Elevated IL-6 signaling plays a critical role in driving articular manifestations of rheumatoid arthritis

Synovial joint damage is mediated by cells of the pannus. In rheumatoid arthritis, there is a marked increase in proliferation, or hyperplasia, of cells of the synovial intimal lining, which include fibroblast-like synoviocytes ( FLS ), osteoclasts, and macrophages.
As a result, the lining increases from a depth of 1 to 2 cells to a depth of 10 to 20 cells.
This expansive synovial tissue is referred to as pannus and directly interfaces with both cartilage and bone of the joint with pathological consequences.

During rheumatoid arthritis progression, FLS along with chondrocytes degrade cartilage, and the pannus invades bone, causing erosion through increased osteoclast activity.

FLS of the synovial intimal, or inner, lining play a key role in chronic inflammation and joint destruction in rheumatoid arthritis.
The invasive properties of FLS have been shown to correlate with radiographic and histological damage in rheumatoid arthritis.

Under normal conditions, FLS secrete proteins that help build the extracellular collagen network, which is responsible for cushioning in joints.
In rheumatoid arthritis, however, FLS:

• Promote inflammatory cell recruitment and activation, as well as angiogenesis, through expression of immunomodulating cytokines and mediators, including IL-6;

• Are the main effectors of cartilage breakdown due to their unique invasive properties and the production of large amounts of matrix metalloproteinases ( MMPs );

• Contribute to bone erosion and systemic osteoporosis through secretion of factors such as receptor activator of nuclear factor kappa B ligand ( RANKL ), which promotes osteoclast differentiation, survival, and activity.

Elevated IL-6 contributes to chronic inflammatory synovitis and promotes joint damage in rheumatoid arthritis by:

• Activating pro-inflammatory cells and mediators both at the joint and extraarticularly, such as neutrophils, macrophages, FLS, T cells, and B cells, and increasing the production of pro-inflammatory molecules, such as cytokines and chemokines;

• Activating and increasing proliferation of FLS. IL-6 both activates and is produced by FLS, establishing a positive feedback loop. FLS in the intimal lining are the primary source of IL-6 in synovial joints, as shown by in situ hybridization and immunohistochemistry studies. Because most synovial cells do not express transmembrane IL-6R in the joint, it is thought that trans-signaling mediates IL-6 effects on synoviocytes;

• Activating Th17 cells, in combination with effects on FLS, sets up a positive feedback loop of IL-6 expression. The combined presence of IL-6 and TGF-beta stimulates naïve T cells to differentiate into Th17 cells. Th17 cells in turn release more IL-6, which further promotes Th17 differentiation. Th17 cells produce IL-17, which also contributes to rheumatoid arthritis pathogenesis, in part by increasing RANKL expression on osteoblasts;

• Stimulating osteoclastogenesis and osteoclast activity, leading to structural damage through bone resorption. There is also evidence that IL-6 and/or sIL-6R may be implicated in the regulation of osteoclast precursors in the bone marrow ( hematopoietic stem cells ) before and during inflammatory arthritis;

• Increasing VEGF levels synergistically with TNF-alpha and IL-1beta. VEGF is central to the formation and maintenance of the pannus through stimulation of angiogenesis;

• Contributing to the shift from acute to chronic inflammation in rheumatoid arthritis. The transition from acute to chronic inflammation in rheumatoid arthritis is characterized by a shift from neutrophil to monocyte infiltration of the synovia.
During acute inflammation, IL-6 is initially released by monocytes, macrophages, and endothelial cells; IL-6 signaling mediates neutrophil recruitment through activation of a subset of chemokines by endothelial cells, and by increasing expression of adhesion molecules on these cells.
Soluble IL-6 receptor is in turn released from neutrophils, which increase the amounts of monocyte-specific, but not neutrophil-specific, chemoattractants secreted by endothelial cells.
It has been proposed that IL-6 and its soluble receptor may regulate the leukocyte recruitment transition through a shift in chemokine production.
During acute inflammation, IL-6 may favor the resolution of the neutrophilic infiltrate and the initiation of the immune response; in chronic inflammation, IL-6 may increase the mononuclear cell infiltrate and participate in disease pathogenesis;

• Regulating B-cell differentiation and autoantibody production. IL-6 stimulates plasmablasts to differentiate into mature plasma cells.
IL-6 can also stimulate antibody production by increasing the production of IL-21 to provide CD4+ T cell mediated B-cell help.
These functions increase B-cell interactions, sustain B-cell survival, and lead to ectopic germinal-center formation in synovial tissue.
Activated mature B cells trigger inflammatory and mesenchymal cells to produce cytokines, chemokines, and other pro-inflammatory factors.
They also produce autoantibodies that contribute to chronic inflammation;

• Activating and targeting the complement system to healthy tissue. Abundant, activated complement is found in the synovial fluid of rheumatoid arthritis patients.
C-reactive protein ( CRP ), a major acute-phase protein induced by IL-6, enhances sIL-6R shedding and can activate the complement system.
Complement, in conjunction with autoantibody immune complexes, places a target on healthy tissues for destruction.
The complement cascade also contributes to inflammation by increasing cytokine production,
Through these diverse mechanisms, IL-6 contributes significantly to the articular pathology associated with rheumatoid arthritis.

Serum IL-6 levels are at their highest in the early morning hours when patients with rheumatoid arthritis particularly experience articular pain and stiffness, as well as functional disability,
This morning stiffness is related to both increased levels of IL-6 and decreased levels of cortisol.
Diurnal variation of IL-6 levels is thought to be controlled at a systemic level through signaling pathways originating from the central circadian clock, and at a local level by autonomous clocks in inflammatory cells and tissues.
In vitro, macrophages and synoviocytes both demonstrate rhythmic IL-6 responses or circadian oscillations.
In humans, levels of cortisol are downregulated during the evening and upregulated in the early morning.
In patients with rheumatoid arthritis, the ratio of serum cortisol to serum pro-inflammatory cytokines is reduced compared with healthy subjects, leading to articular pain and stiffness in the early morning, when IL-6 levels are increased. ( Xagena )

Source: Leonard H. Calabrese, Ernest Choy, The contributions of IL-6 to disease manifestations of rheumatoid arthritis, 2015

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