Free shipping starts now, no minimum!

The Role of ASIC3 in Skin Fibrosis: A Feedback Loop That Goes Beyond Scar Formation

Skin fibrosis, which typically shows up as hypertrophic scars or keloids, is an issue beyond just cosmetic concern. The skin is a complex organ that involves a plethora of events involving collagen fibers, extracellular matrix proteins, and various cell types like macrophages and fibroblasts. For a long time, scientists have tried to understand the mechanisms behind fibrosis, and it seems that an inflammatory environment in the skin is to be a key driver, but the molecular minutiae of this interaction have remained largely obscure.

But another intriguing element in this complex puzzle is the role of acid-sensing ion channels (ASICs). A recent study published in Nature’s Cell Death and Disease took a closer look at ASIC3, one specific member of the ASIC family. The researchers delved into how ASIC3 interacts with fibroblasts and macrophages – two central players in skin fibrosis.

Fibrosis and ASIC3 expression

Researchers first examined the differential expression of ASICs in samples of fibrotic tissues. They found that ASIC3 mRNA levels were noticeably upregulated in cutaneous fibrotic connective tissue. Interestingly, other ASIC family members did not show significant changes in expression. Further investigations using hematoxylin and eosin (H&E) staining revealed that both hypertrophic scar and keloid tissues had a thicker epidermis than normal skin. Immunofluorescence and immunohistochemistry using an Anti-ASIC3 Antibody (#ASC-018) from Alomone Labs corroborated these findings, revealing increased ASIC3 expression in diseased tissue compared to normal skin (Figure 1).

Subsequent tests, including western blot and immunofluorescence, provided additional layers of evidence. ASIC3 protein expression was markedly higher in fibrotic tissues compared to normal skin. Importantly, ASIC3 mRNA and protein expression levels were significantly increased in hypertrophic keloids and keloid-derived fibroblasts. Moreover, a positive correlation was found between elevated levels of ASIC3 and collagen expression in keloids. This suggests that ASIC3 may function as an acid sensor in the acidic environment of skin inflammation, implicating its role in the causality of skin fibrosis.

ASIC3 is highly expressed in human hypertrophic scar and keloid tissues

Figure 1. A Schematic diagram of sample source and experimental analysis. B Representative H&E staining images of human normal skin, hypertrophic scar (HS), and keloid. Scale bars, 100 μm. C Immunohistochemistry of ASIC3 expression in normal skin, hypertrophic scar and keloid. Scale bars, 100 μm and 50 μm. D Immunofluorescence analysis of ASIC3 (red) (Anti-ASIC3 Antibody (#ASC-018), Alomone Labs) and vimentin (green) expression in human normal skin, hypertrophic scar, and keloid. Scale bars, 100 μm and 50 μm. E Western blot analysis of ASIC3 expression in normal skin, hypertrophic scar, and keloid. GAPDH served as loading control (n = 3). F Immunofluorescence analysis of ASIC3 (red) (Anti-ASIC3 Antibody (#ASC-018), Alomone Labs) and vimentin (green) expressions in fibroblasts derived from normal skin, hypertrophic scar, and keloid. Scale bars, 50 μm. G MFI quantification of ASIC3 in (F) (n = 3). Data are expressed as the means ± SD. **P < 0.01 and ***P ≤ 0.001 compared with normal skin. HS, hypertrophic scar; ASIC3, acid-sensing ion channel 3; DAPI, 4′,6-diamidino-2-phenylindole; IHC, immunohistochemistry; IF, immunofluorescence; GAPDH, glyceraldehyde-3-phosphate dehydrogenase. Figure and legend from Wu, JJ. et al. Cell Death Dis 13, 527 (2022).

A Paracrine Loop in Action

ASIC3 is not just another molecule on the block. It has shown significant variations in its expression between fibrotic and normal tissues, and has caught scientists’ attention for its potential role in skin fibrosis. In this study, researchers found that activating the ASIC3 channel boosts the local aggregation of M2 macrophages – a specific type of macrophage involved in tissue repair – and fosters skin fibrosis. Once in the skin, these macrophages enter a paracrine loop with fibroblasts that stimulates fibroblast differentiation into myofibroblasts, a key event in scar formation.

What’s compelling is the discovery that ASIC3 regulates the secretion of macrophage colony-stimulating factor (M-CSF) by fibroblasts. In turn, M2 macrophages, guided by the ASIC3-M-CSF signal, promote the production of alpha-smooth muscle actin (α-SMA)-positive fibroblasts. This process further fuels the feedback loop, contributing to the fibrotic pathway.

The Profibrotic Role of TGF-β1

Transforming growth factor β1 (TGF-β1), a profibrotic cytokine, also makes an appearance in this developing picture. The study reveals that ASIC3 activation didn’t directly influence TGF-β1 expression in fibroblasts, but it did only when macrophages were co-cultured with fibroblasts. This strongly indicates that TGF-β1 plays a part in the feedback loop, solidifying its place in the fibrotic pathway.

New Paths for Intervention?

The findings strongly suggest that ASIC3 is a promising target for treating skin fibrosis. The study revealed that ASIC3 regulates a feedback loop involving M-CSF and M2 macrophages, which then modulates the differentiation of fibroblasts into myofibroblasts. As we look ahead, questions still linger: Could targeting ASIC3 disrupt this feedback loop and offer a new therapeutic avenue for skin fibrosis? 

While answers to these questions await further studies, what’s certain is that the research has added an important layer to our understanding of skin fibrosis at a molecular level.