Soluble CD163 is a potential biomarker in systemic sclerosis

KEYWORDS:

• Biomarkers
• M2 macrophage
• soluble CD163
• systemic sclerosis

1. Introduction

Systemic sclerosis (SSc) is a fibrotic disease characterized by immunologic abnormalities, vascular injury, and increased accumulation of extracellular matrix (ECM) proteins, which are produced by myofibroblasts, in the skin and internal organs [1]. Over 90% of SSc patients are positive for autoantibodies, including anti-DNA topoisomerase I, anti-centromere, and anti-RNA polymerase antibodies. SSc is classified into two subsets based on the extent of skin sclerosis: diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc (lcSSc) [2]. Patients with dcSSc, a severe type of SSc, frequently display severe internal organ manifestations, including interstitial lung disease (ILD), heart disease, and scleroderma renal crisis. By contrast, patients with lcSSc, a mild form of SSc, display mild internal organ manifestations including gastrointestinal involvement and ILD, although pulmonary arterial hypertension (PAH) can manifest at a later stage. These SSc classifications are beneficial for the selection of treatments and prediction of the involvement of internal organs and disease prognosis; however, the fibrotic features of SSc are difficult to treat, leading to considerable morbidity and mortality. Additionally, it is difficult to recover from the disability upon development of extensive tissue fibrosis or severe vascular injury. Unfortunately, effective treatment for SSc has not been established. Although the pathways associated with SSc pathogenesis remain unclear, immune cells and their components contribute to SSc development, with most of the infiltrating cells in the skin of patients with SSc representing activated T cells and macrophages.

2. M1 and M2 macrophages

Monocytes circulate in the blood, and upon their extravasation through the endothelium, differentiate into macrophages. Macrophages distribute into almost all tissues and play important roles, including antigen presentation, phagocytosis, and maintenance of tissue homeostasis, in innate immunity against pathogens. Naïve (M0) macrophages subsequently become activated macrophages in response to infection and tissue inflammation, with these macrophages divided into two opposing subsets: classically activated (M1) macrophages and alternatively activated (M2) macrophages. M1 macrophage differentiation is facilitated by microbial products, such as lipopolysaccharide (LPS), or proinflammatory cytokines, such as interferon-γ. M1 macrophages exhibit a potent ability to kill pathogens and promote inflammation, potentially resulting in aberrant inflammation. By contrast, M2 macrophages negatively regulate aberrant inflammation and repair injured tissues to encourage homeostasis. Additionally, M2 macrophages can induce fibrosis of various tissues by promoting collagen synthesis and remodeling [3]; however, overactive M2 macrophages can promote the onset of fibrotic diseases. M2 macrophage differentiation is facilitated by T helper (Th)2 cytokines, such as interleukin (IL)-4 and IL-13, which are elevated in the serum of patients with SSc [4]. Furthermore, Th2 cytokines play a distinctive role in SSc pathogenesis [4], with previous studies suggesting that dysregulated Th2 cytokine levels in SSc promote M2 macrophage differentiation, thereby resulting in aberrant tissue fibrosis. M2 macrophages are also closely associated with pathogenesis of other connective tissue diseases, such as systemic lupus erythematosus, dermatomyositis, polymyositis, and rheumatoid arthritis. Collectively, these results suggest that M2 macrophages have a distinctive role for the pathogenesis of connective tissue diseases.

3. M2 macrophages in SSc

M2 macrophages express CD163 as a scavenger receptor involved in the removal of necrotic cells, apoptotic cells, cell debris, and opsonized pathogens. Therefore, CD163 is thought to represent an M2 macrophage marker. The primary function of CD163 is uptake of circulating haptoglobin–hemoglobin complexes from circulating blood [5]. Additionally, CD163 is a receptor for ADAMTS13 and tumor necrosis factor-like weak inducer of apoptosis (TWEAK). Soluble CD163 (sCD163) is released from the cell surface of M2 macrophages by proteolysis in response to oxidative stress or inflammatory stimuli and exerts anti-inflammatory effects by inhibiting T cell proliferation [6]. In SSc patients, levels of CD14⁺ monocytes in the blood are significantly increased relative to those observed in healthy controls, and CD14⁺ monocytes in SSc patients display elevated expression of CD163 [7]. Moreover, number of CD163⁺ M2 macrophages in the skin of SSc patients are significantly elevated relative to those in healthy controls [7]. Furthermore, circulating monocytes in SSc patients having ILD exhibit increased CD163 expression in response to LPS stimulation as compared with those in normal controls [8], with another study reporting elevated CD163 mRNA levels in SSc patients with ILD relative to those in healthy controls, being positively associated with ILD severity [9]. These findings represent emerging evidence that M2 macrophages play a distinctive role in SSc pathogenesis.

4. sCD163 in SSc

Nakayama et al [10] first reported significantly elevated serum sCD163 levels in patients with SSc relative to those in healthy controls, suggesting that sCD163 represents a potential biomarker for SSc. Additionally, SSc patients with elevated serum sCD163 levels present significantly higher right ventricular systolic pressure and lower carbon monoxide diffusing capacity (%DLCO) levels, as well as a shorter duration of disease, as compared with normal individuals. Therefore, serum sCD163 levels were also suggested as a biomarker for early stage PAH, which represents a major cause of SSc-related death, in patients with SSc [10]. Moreover, Hassan et al [11] reported that serum sCD163 levels in patients with both dcSSc and lcSSc are significantly elevated relative to those in healthy controls, and that SSc patients with elevated serum sCD163 levels present significantly higher pulmonary artery systolic pressure (PASP) than those with normal levels. Furthermore, they reported that serum sCD163 levels are positively correlated with PASP in patients with SSc [11]. 

A previous study reported that serum sCD163 levels in SSc patients with ILD are significantly elevated as compared with those observed in patients without ILD, and that serum sCD163 levels are positively correlated with the pulsatility index, which is used to determine renal vascular damage [12]. Additionally, another study reported significantly increased ex vivo production of sCD163 by peripheral blood mononuclear cells (PBMCs) from patients with SSc relative to that observed in PBMCs from healthy controls [13]. Moreover, this study showed that serum sCD163 levels in SSc patients with progressively worsening disease were also significantly elevated as compared with those in SSc patients with stable disease and which were comparable with levels in healthy controls [13]. These results indicate that sCD163 production by PBMCs potentially represents a biomarker of disease progression in SSc [13]. Although serum levels of soluble TWEAK (sTWEAK), a counterpart of CD163, were comparable between SSc patients and healthy controls, serum levels of sCD163 and the sCD163/sTWEAK ratio were significantly elevated in SSc patients as compared with these indices in healthy controls [14]. Additionally, this study reported that a higher sCD163/sTWEAK ratio, but not serum sCD163 level, was associated with the severity of skin sclerosis in SSc, whereas both higher sCD163/sTWEAK ratio and serum sCD163 level were associated with a lower risk of digital ulcers (DUs) in SSc patients [14]. However, a previous report indicated that serum sCD163 levels in patients with SSc and DUs were significantly elevated relative to those in SSc patients without DUs [11]. This discrepancy might have been due to the small sample size. Notably, Frantz et al [15] confirmed that serum sCD163 levels in 203 patients with SSc were significantly elevated as compared with those of healthy controls in a study using a larger sample, although sCD163 could not emerge as a useful biomarker for specific SSc-related clinical manifestations. These findings support sCD163 as a potential biomarker in SSc.

5 Conclusion and perspective

Numerous studies have provided evidence that M2 macrophages play a disease-promoting role in SSc pathogenesis, and suggest that CD163 represents a potential biomarker in SSc. However, further studies are required to investigate the exact role of M2 macrophages and CD163 in SSc pathogenesis and to determine the potential therapeutic efficacy of strategies targeting M2 macrophages and CD163 in SSc.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewers Disclosure

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.