Illustration of systemic sclerosis and related research.

Systemic Sclerosis Unveiled: How Hyaluronan and M2 Macrophages Contribute to Skin Fibrosis

Elliot Brynn in Health & Wellness August 2025 • 4 min read.

"New research sheds light on the roles of hyaluronan and M2 macrophages in systemic sclerosis, offering potential therapeutic targets for this challenging autoimmune disease."

Systemic sclerosis (SSc), also known as scleroderma, is a chronic autoimmune disease primarily characterized by fibrosis, or the thickening and scarring of skin and internal organs. This condition is not only debilitating but also challenging to treat, as its underlying mechanisms are complex and not fully understood.

Two recent studies published in Annals of the Rheumatic Diseases have illuminated key aspects of SSc, focusing on the roles of hyaluronan and M2 macrophages in the disease process. These findings offer new perspectives on potential therapeutic interventions.

This article breaks down these studies, explaining their findings in accessible language and highlighting their significance for individuals affected by SSc and those interested in autoimmune diseases.

Hyaluronan's Role in Systemic Sclerosis: What's the Connection?

Illustration of systemic sclerosis and related research.

Hyaluronan (HA) is a major component of the extracellular matrix (ECM), the substance that fills the spaces between cells in tissues. It's a glycosaminoglycan, a type of complex carbohydrate, and plays a crucial role in tissue repair, inflammation, and remodeling. Enzymes called hyaluronan synthases (HAS1-3) produce HA, while hyaluronidases (HYAL1-2) break it down. Different molecular weights of HA exert different effects on the body.

A study by Kilic et al. investigated the levels of hyaluronan in patients with SSc. The researchers found:

Significantly elevated serum hyaluronan levels in SSc patients compared to healthy controls.
Higher serum hyaluronan levels in postmenopausal women with SSc compared to premenopausal women with SSc.
Increased hyaluronan accumulation in skin tissue samples from SSc patients.
Elevated HAS-2 mRNA expression (responsible for HA production) in SSc skin samples, while HYAL-2 mRNA expression (responsible for HA degradation) was decreased.

These findings suggest that in SSc, there's an overproduction of hyaluronan coupled with a decreased breakdown, leading to its accumulation in the skin and serum. This hyaluronan accumulation likely contributes to the fibrosis characteristic of SSc.

Translating Research into Potential Treatments for SSc

These studies collectively highlight the complex interplay of immune cells and extracellular matrix components in the pathogenesis of systemic sclerosis. By identifying key players like hyaluronan and M2 macrophages, researchers are paving the way for more targeted and effective therapies.

Further research is needed to fully understand the mechanisms by which hyaluronan and M2 macrophages contribute to fibrosis in SSc. However, these findings suggest that targeting these molecules could be a promising therapeutic strategy. For example, inhibiting HAS-2 to reduce hyaluronan production or modulating M2 macrophage activity could potentially alleviate fibrosis and improve outcomes for patients with SSc.

While challenges remain, these discoveries offer hope for the development of new treatments that can address the underlying causes of this debilitating condition and improve the quality of life for those living with SSc.

About this Article -

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Everything You Need To Know

What exactly is systemic sclerosis (SSc), and what makes it so challenging to treat?

Systemic sclerosis, also known as scleroderma, is a chronic autoimmune disease distinguished by fibrosis, the thickening and scarring of the skin and internal organs. The underlying mechanisms are complex and not fully understood. Research indicates key roles for hyaluronan and M2 macrophages in the disease process. These elements present new perspectives for potential therapeutic interventions.

What is the role of hyaluronan in systemic sclerosis, and how do hyaluronan synthases (HAS1-3) and hyaluronidases (HYAL1-2) factor into this?

Hyaluronan, a major component of the extracellular matrix, is produced by hyaluronan synthases (HAS1-3) and broken down by hyaluronidases (HYAL1-2). In systemic sclerosis, the balance shifts due to elevated HAS-2 mRNA expression and decreased HYAL-2 mRNA expression. This imbalance leads to hyaluronan accumulation which contributes to skin fibrosis.

What are M2 macrophages, and how do they contribute to the development of fibrosis in systemic sclerosis?

M2 macrophages are a type of immune cell that influences fibrosis and tissue remodeling. While not explicitly detailed here, M2 macrophages are present in higher quantities in SSc patients. They are linked to the progression of fibrosis, suggesting that modulating M2 macrophage activity could potentially reduce the severity of systemic sclerosis.

What did the Kilic et al. study reveal about hyaluronan levels and their relationship to systemic sclerosis?

The study by Kilic et al. found significantly elevated serum hyaluronan levels in individuals with systemic sclerosis compared to healthy individuals. Furthermore, postmenopausal women with systemic sclerosis exhibited higher serum hyaluronan levels than premenopausal women with the same condition. Skin tissue samples from individuals with systemic sclerosis also displayed increased hyaluronan accumulation, with HAS-2 mRNA expression elevated and HYAL-2 mRNA expression decreased.

Given the roles of hyaluronan and M2 macrophages, what potential therapeutic strategies are being explored for systemic sclerosis?

Targeting hyaluronan and M2 macrophages offers potential therapeutic avenues. For hyaluronan, strategies could focus on inhibiting hyaluronan synthases (HAS1-3) or promoting hyaluronidase (HYAL1-2) activity to reduce hyaluronan accumulation. For M2 macrophages, research might explore ways to modulate their activity to prevent or reverse fibrosis. These approaches could lead to more effective treatments for systemic sclerosis.