CXCL10 belongs to the ELR− CXC subfamily chemokine. CXCL10 exerts its function through binding to chemokine (C–X–C motif) receptor 3 (CXCR3), a seven trans-membrane receptor coupled to G proteins. CXCL10 is also named 10 kDa IP-10, as its secretion by cluster of differentiation (CD)4+, CD8+, natural killer (NK) and NK-T cells is dependent on IFN-γ, which is itself mediated by the interleukin (IL)-12 cytokine family. CXCL10 is secreted by several cell types, including T lymphocytes, neutrophils, monocytes, splenocytes, endothelial cells, fibroblasts, keratinocytes, thyrocytes, preadipocytes, etc. Recruited Th1 lymphocytes may be responsible for enhanced IFN-γ and tumor necrosis factor (TNF)-α production,which in turn stimulates CXCL10 secretion froma variety of cells, therefore creating an amplification feedback loop.
Recent reports have shown that the serum and/or the tissue expressions of CXCL10 are increased in organ specific autoimmune diseases, such as autoimmune thyroiditis (AT), Graves' disease (GD), and type 1 diabetes (T1D), or systemic rheumatological disorders like rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and cryoglobulinemia.
CXCL10 in Type 1 diabetes (T1D): Several studies show that CXCL10 is highly expressed in lymphocytes infiltrating the human islet, and that β-cells, under the influence of cytokines (such as IFN-γ and TNF-α), can modulate the autoimmune response through the production of CXCL9/monokine induced by IFN-γ (MIG), CXCL10 and CXCL11 chemokines. These chemokines can induce the migration of Th1 lymphocytes into the islet, which in turn, secrete more IFN-γ and TNF-α, stimulating the chemokine production by the target cells, thus initiating and perpetuating the autoimmune cascade. Furthermore, CXCL10 was identified as the dominant chemokine expressed in vivo in the islet environment of prediabetic animals and T1D patients.
CXCL10 in autoimmune thyroiditis (AT): It has been postulated that CXCL10 could be a marker of a stronger and more aggressive inflammatory response in the thyroid, subsequently leading to thyroid destruction and hypothyroidism. These findings are in line with experimental evidence demonstrating that a Th1 enriched micro-environment leads to a more severe course of thyroiditis resulting in thyrocyte apoptosis and hypothyroidism. Other studies have shown a strong correlation between circulating CXCL9 or CXCL11 and CXCL10 in AT patients. These results underline the importance of a Th1 immune attack in the initiation of AT.
CXCL10 in Graves' disease (GD): Circulating CXCL10 levels (sCXCL10) is high in patients with GD, in comparison with age- and sex-matched patient controls. Hyperthyroid GD had significantly higher sCXCL10 than euthyroid or hypothyroid GD (145 ± 92, 107 ± 56 and 105 ± 46 pg/mL, respectively; p = 0.01). GD patients with untreated hyperthyroidism had higher sCXCL10 than hyperthyroid or euthyroid GD patients undermethimazole (MMI) treatment. Comparable sCXCL10 were observed in newly diagnosed untreated hyperthyroid GD patients with respect to untreated patients with relapse of hyperthyroidism after a previous MMI course. These results suggested that sCXCL10 are associated with the active phase of GD in both newly diagnosed and relapsing hyperthyroid patients.
CXCL10 in Graves' ophthalmopathy (GO): sCXCL10 were measured in patients with active or inactive GO, and the effects of IFN-γ and TNF-α stimulation on CXCL10 secretion in primary cultures of thyrocytes, orbital fibroblasts, and preadipocytes were tested. Among GO patients, sCXCL10 were significantly higher in those with active disease than in those with inactive disease.
CXCL10 in Rheumatoid arthritis (RA): CXCL10 has been detected in sera, synovial fluid (SF), and synovial tissue (ST) in RA patients. It was also found that serum and tissue levels of CXCL10 were increased in collagen-induced arthritis (CIA), an animal model of RA. Available evidence shows that nuclear factor kappa-B ligand (RANKL) promotes CXCL10 expression in osteoclast precursors, and that CXCL10 mediates RANKL expression in CD4+ T cells via Gαi subunit of CXCR3 in RA synovium. Importantly, this cross-talk between CXCL10 and RANKL, or other cytokines such as TNF-α may be responsible for the initiation and/or aggravation of inflammation and bone erosion in RA.
CXCL10 and its receptor, CXCR3, appear to contribute to the pathogenesis of many autoimmune diseases, organ specific (such as T1D, AT, GD and GO), or systemic (such as AR, PsA, SLE, MC, SS, or SSc).
The secretion of CXCL10 by CD4+, CD8+, NK and NK-T cells is dependent on IFN-γ, which is itself mediated by the IL-12 cytokine family. Under the influence of IFN-γ, CXCL10 is secreted by several cell types including endothelial cells, fibroblasts, keratinocytes, thyrocytes, preadipocytes, etc. Determination of high level of CXCL10 in peripheral liquids is therefore a marker of host immune response, especially in Th1 orientated T-cells. In tissues, recruited Th1 lymphocytes may be responsible for enhanced IFN-γ and TNF-α production, which in turn stimulates CXCL10 secretion from a variety of cells, therefore creating an amplification feedback loop, and perpetuating the autoimmune process.
Antonelli A, et al. Chemokine (C–X–C motif) ligand (CXCL) 10 in autoimmune diseases[J]. Autoimmunity reviews, 2014, 13(3): 272-280.