Chemokine (C–X–C motif) ligand (CXCL)10 in autoimmune diseases

doi:10.1016/j.autrev.2013.10.010

Autoimmunity Reviews

Volume 13, Issue 3, March 2014, Pages 272-280

https://doi.org/10.1016/j.autrev.2013.10.010 Get rights and content

Highlights

•
The involvement of CXCR3 and CXCL10 in many autoimmune diseases is demonstrated.
•
High CXCL10 level in peripheral liquids is a marker of host Th1 immune response.
•
IFNγ/TNFα stimulates a variety of cells to produce CXCL10 recruiting Th1 lymphocytes.
•
Studies are evaluating CXCL10 as a novel therapeutic target in autoimmune diseases.

Abstract

(C–X–C motif) ligand (CXCL)10 (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 and its receptor, CXCR3, appear to contribute to the pathogenesis of many autoimmune diseases, organ specific (such as type 1 diabetes, autoimmune thyroiditis, Graves' disease and ophthalmopathy), or systemic (such as rheumatoid arthritis, psoriatic arthritis, systemic lupus erythematosus, mixed cryoglobulinemia, Sjögren syndrome, or systemic sclerosis).

The secretion of CXCL10 by cluster of differentiation (CD)4 +, CD8 +, natural killer (NK) and NK-T cells is dependent on interferon (IFN)-γ, which is itself mediated by the interleukin-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 fluids is therefore a marker of host immune response, especially T helper (Th)1 orientated T-cells. In tissues, recruited Th1 lymphocytes may be responsible for enhanced IFN-γ and tumor necrosis factor-α production, which in turn stimulates CXCL10 secretion from a variety of cells, therefore creating an amplification feedback loop, and perpetuating the autoimmune process.

Further studies are needed to investigate interactions between chemokines and cytokines in the pathogenesis of autoimmune diseases and to evaluate whether CXCL10 is a novel therapeutic target in various autoimmune diseases.

Introduction

(C–X–C motif) ligand (CXCL)10/interferon (IFN)-γ-induced protein 10 (IP-10) belongs to the CXC subfamily chemokine containing a single and variable amino acid between the two first of four highly conserved cysteine residues. The CXC chemokines can be divided into two subgroups according to the presence of the ELR motif or Glu–Leu–Arg. The ELR⁺ CXC chemokines are potent promoter of angiogenesis, whereas the ELR⁻ chemokines, such as CXCL10, display angiostatic properties [1]. 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 [2].

Under the influence of cytokines, CXCL10 is secreted by several cell types, including T lymphocytes, neutrophils, monocytes, splenocytes, 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 T helper (Th)1 orientated T-cells.

Recruited Th1 lymphocytes may be responsible for enhanced IFN-γ and tumor necrosis factor (TNF)-α production, which in turn stimulates CXCL10 secretion from a variety of cells, therefore creating an amplification feedback loop [3].

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) [3], or systemic rheumatological disorders like rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), and cryoglobulinemia [4].

Here, we review CXCL10 in the abovementioned autoimmune disorders.

Section snippets

Type 1 diabetes (T1D)

T1D is an immunologically mediated disease. Prevention and treatment of T1D is hampered by the fact that the key immunological mechanisms of the pathogenesis of the disease are still under debate [5], [6].

However, the involvement of a Th1 immune response in the β-cell destruction has been shown [7].

The evaluation of circulating levels of CXCL10 in T1D produced different results. High levels of serum CXCL10 was observed in children and adults with T1D by most of the studies, in particular in

CXCL10 in autoimmune thyroiditis (AT)

AT, also known as chronic lymphocytic or Hashimoto's thyroiditis, is characterized by infiltration of the thyroid gland by inflammatory cells and production of autoantibodies to thyroid-specific antigens thyroglobulin and thyroperoxidase [21]. It is accompanied by hypothyroidism due to destruction and eventual fibrous replacement of the follicle cells. AT is clearly multifactorial in etiology with genetic and environmental factor contributions [22].

By using immunohystochemistry, a statistically

CXCL10 in Graves' disease (GD)

Thyrotropin receptor autoantibodies of the stimulating variety are the hallmark of GD [44], [45].

Although GD is considered an autoantibody-mediated, Th2-dominant disease, Th1-dominance may prevail in its initial phase [46].

In GD CXCR3 receptor was found to be highly expressed in endothelial cells as well as in infiltrating inflammatory cells, while CXCL10/IP-10 was observed not only on these cells, but also on thyrocytes [23].

Another study demonstrates that the CXCR3-binding chemokine

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. In primary cultures of retrobulbar fibroblasts and retrobulbar preadipocytes from GO patients, CXCL10 production was absent under basal conditions; dose-dependent

Targeting CXCR3 and CXCL10 in thyroid autoimmunity

There are several models of intervention for interfering with the chemokine system which are represented by small antagonist molecules, modified chemokines, neutralizing monoclonal antibodies, binding proteins [63].

However, the efforts aimed at the pharmacological use of the abovementioned models have encountered major hurdles, which have delayed the development of anti-chemokine agents with anti-inflammatory properties. For these reasons, many studies have evaluated the possibility of

Rheumatoid arthritis (RA)

RA is chronic inflammatory arthritis characterized by joint inflammation, synovial hyperplasia, and bone destruction. A Th1/Th2 cytokine imbalance with a predominance of Th1 cytokines, including IFN-γ has been suggested to be of pathogenetic importance in RA [74], [75].

CXCL10 has been detected in sera, synovial fluid (SF), and synovial tissue (ST) in RA patients [76].

CXCL10 is mainly expressed by infiltrating macrophage-like cells and fibroblast-like synoviocytes in RA synovium [77].

CXCR3 is

CXCL10 expression in other inflammatory arthritis

Juvenile idiopathic arthritis (JIA) is characterized by persistent accumulation of T lymphocytes in the synovial membrane and the Th1 cytokine profile [81]. The expression of CXCL10 is increased in synovial macrophage, and endothelial cells in JIA. CXCR3 is also expressed at high density by T cells isolated from SF and synovial membrane in JIA [82]. PsA is an inflammatory joint disease associated with psoriasis of unknown pathogenesis. It has been reported that the serum level of CXCL10 in PsA

CXCL10 and systemic lupus erythematosus (SLE)

SLE is a chronic inflammatory autoimmune disease with variable clinical manifestations that is associated with the presence of multiple autoantibodies. Peripheral blood lymphocytes in patients with SLE show Th2-like profiles [85], though Th1 cells and IFN-γ have been shown to be important for the development of SLE [86].

Some studies reported that CXCR3 is expressed by a majority of the infiltrating CD4 + and CD8 + T cells in several types of cutaneous damages associated with lupus, and that the

Mixed cryoglobulinemia (MC)

MC is usually classified among systemic vasculitis, in the setting of small vessel vasculitides; therefore, MC syndrome and cryoglobulinemic vasculitis are referred to the same clinico-pathological condition. Cryoglobulinemic vasculitis is characterized by a typical clinical triad (purpura, weakness, arthralgias) and multisystem organ involvement. Reduced hemolytic complement activity, with the typical pattern of low or undetectable C4, is typically found; however, both complement levels and

CXCL10 and Sjögren syndrome (SS)

SS is characterized by a dry mouth, dry eyes, and salivary and lacrimal gland inflammation. Mononuclear cell infiltration of salivary and lacrimal glands results in the destruction of epithelial cells, the degeneration of surrounding tissue, and diminished secretion. Infiltrating inflammatory cells consist predominantly of CD4 + T cells, with smaller numbers of CD8 + cells, B cells, and plasma cells around ductal tissues [132].

The expressions of Th1-associated chemokines (CXCL9, CXCL10, and

CXCL10 and systemic sclerosis (SSc)

SSc is a relatively rare autoimmune disease characterized by Raynaud's phenomenon and progressive skin thickening, but often involves internal organs, such as the lungs, gastrointestinal tract, and kidneys, and may result in loss of organ function. Endothelial cell injury caused by ischemia–reperfusion may induce inflammatory cell infiltration and subsequent cytokine production leading to tissue fibrosis. During this process, chemokines may importantly mediate leukocyte chemotaxis and

Conclusion

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.

Take-home messages

•
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.
•
Further studies are needed to investigate interactions between chemokines and cytokines in the pathogenesis of autoimmune diseases and to evaluate whether CXCL10 is a novel therapeutic target in various autoimmune diseases.

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ReviewChemokine (C–X–C motif) ligand (CXCL)10 in autoimmune diseases

Highlights

Abstract

Introduction

Section snippets

Type 1 diabetes (T1D)

CXCL10 in autoimmune thyroiditis (AT)

CXCL10 in Graves' disease (GD)

CXCL10 in Graves' ophthalmopathy (GO)

Targeting CXCR3 and CXCL10 in thyroid autoimmunity

Rheumatoid arthritis (RA)

CXCL10 expression in other inflammatory arthritis

CXCL10 and systemic lupus erythematosus (SLE)

Mixed cryoglobulinemia (MC)

CXCL10 and Sjögren syndrome (SS)

CXCL10 and systemic sclerosis (SSc)

Conclusion

Take-home messages

Autoimmun Rev

Autoimmun Rev

Autoimmun Rev

Autoimmun Rev

Autoimmun Rev

Diabetes Metab Res Rev

Autoimmun Rev

J Clin Endocrinol Metab

J Clin Endocrinol Metab

Metabolism

J Interferon Cytokine Res

Mod Rheumatol

Autoimmun Rev

Exp Clin Endocrinol

Clin Endocrinol

J Clin Endocrinol Metab

J Immunol

Int Immunol

Gastroenterology

Exp Cell Res

J Biol Chem

Nature

Arthritis Res Ther

J Pathol

Ann Rheum Dis

Autoimmun Rev

Arthritis Rheum

Curr Opin Rheumatol

CXC chemokines in angiogenesis

J Leukoc Biol

Anticancer properties of the IL-12 family—focus on colorectal cancer

Curr Med Chem

Elevated serum IP-10 levels observed in type 1 diabetes

Diabetes Care

Serum concentrations of the interferon-gamma-inducible chemokine IP-10/CXCL10 are augmented in both newly diagnosed type I diabetes mellitus patients and subjects at risk of developing the disease

Diabetologia

Two cases of “fulminant” type 1 diabetes suggesting involvement of autoimmunity

Ann N Y Acad Sci

Serum titres of anti-glutamic acid decarboxylase-65 and anti-IA-2 autoantibodies are associated with different immunoregulatory milieu in newly diagnosed type 1 diabetes patients

Clin Exp Immunol

Serum concentrations of the interferon-alpha-inducible chemokine IP-10/CXCL10 are augmented in both newly-diagnosed type I diabetes mellitus patients and subjects at risk of developing the disease

Diabetologia

Diabetologia

Altered chemokine levels in individuals at risk of type 1 diabetes mellitus

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Serum Th1 (CXCL10) and Th2 (CCL2) chemokine levels in children with newly diagnosed Type 1 diabetes: a longitudinal study

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Review
Chemokine (C–X–C motif) ligand (CXCL)10 in autoimmune diseases