Mechanism study of chemokine CCL1/I-309 driving pulmonary fibrosis progression through the AMFR-SPRY1 signaling axis

I. Research Background and Scientific Questions

Pulmonary Fibrosis (PF) is a chronic, progressive disease characterized by excessive deposition of extracellular matrix and structural destruction in lung tissue. The core pathological process involves the activation of lung fibroblasts and their differentiation into myofibroblasts. As key effector cells, myofibroblasts secrete large amounts of collagen, driving the fibrotic process. Currently, effective treatments for PF remain limited. Chemokines play a central role in mediating immune cell recruitment and inflammatory responses, but some chemokines have also been found to directly act on non-immune cells (e.g., fibroblasts), participating in tissue repair and fibrosis. This study focuses on the chemokine CCL1 (also known as I-309), aiming to systematically elucidate its specific role and molecular mechanisms in the development and progression of pulmonary fibrosis.

II. Research Tools: The Key Role of CCL1/I-309 Protein in Mechanism Studies

To deeply analyze the biological functions of CCL1, high-purity, high-activity CCL1/I-309 protein is an essential research tool. This recombinant protein can be used for:

1. In vitro functional validation: Directly stimulating lung fibroblasts to mimic its role in the fibrotic microenvironment, observing its effects on cell migration, proliferation, α-smooth muscle actin (α-SMA) expression (a marker of myofibroblast transformation), and collagen synthesis.

2. Receptor binding and signaling pathway studies: Investigating the binding properties of CCL1 with potential receptors (e.g., the newly discovered AMFR in this study) and its activation of downstream signaling pathways (e.g., ERK-p70S6K).

3. Animal model-assisted research: Serving as an exogenous stimulant to evaluate whether it can induce or exacerbate fibrotic phenotypes in lung tissue in vivo.

III. The Role and Mechanism of CCL1 in Pulmonary Fibrosis

This study systematically revealed the pro-fibrotic role of CCL1 and its signaling pathway by constructing bleomycin- and silica-induced mouse pulmonary fibrosis models and combining cellular and molecular biology techniques.

1. Upregulation of CCL1 in pulmonary fibrosis: In two different etiological mouse models of pulmonary fibrosis, significantly elevated CCL1 protein levels were detected in bronchoalveolar lavage fluid (BALF) and lung tissues. Further analysis indicated that alveolar macrophages and CD4+ T cells are the primary sources of CCL1.

2. CCL1 directly drives fibroblast activation and fibrosis: The study found that exogenous administration of CCL1 was sufficient to promote lung tissue fibrosis. In vitro experiments confirmed that CCL1 could directly induce lung fibroblast migration and promote their differentiation into myofibroblasts and extracellular matrix protein synthesis.

3. Identification of the novel receptor AMFR and signaling transduction mechanism: The study first discovered that CCL1 does not act through traditional chemokine receptors but interacts with the cell membrane protein autocrine motility factor receptor (AMFR, a membrane protein with E3 ubiquitin ligase activity) to activate fibroblasts. Further mechanistic studies revealed:

- Signal cascade: After CCL1-AMFR binding, the ERK-p70S6K signaling cascade is activated, driving the transcription and protein synthesis of fibrosis-related genes.

- Key node regulation: The study found that CCL1 induces the translocation of SPRY1 protein from the cytoplasm to the plasma membrane. On the membrane, AMFR, as an E3 ligase, regulates SPRY1, while membrane-localized SPRY1 recruits RasGAP and limits its contact with Ras, thereby relieving the inhibition of the Ras-ERK signaling pathway and ultimately leading to sustained activation of ERK signaling, amplifying the fibrotic signal transduction.

IV. Research Significance and Translational Prospects

This study is the first to systematically reveal the new mechanism by which the chemokine CCL1, through the non-classical receptor AMFR and the SPRY1-regulated ERK-p70S6K signaling axis, directly drives lung fibroblast activation and fibrosis progression. This discovery not only deepens the understanding of the molecular network of pulmonary fibrosis pathogenesis but, more importantly, identifies CCL1/I-309 protein and key nodes in its signaling pathway (e.g., CCL1, AMFR, SPRY1) as potential therapeutic targets. Inhibitors targeting this pathway (e.g., CCL1 neutralizing antibodies, AMFR or downstream signaling molecule inhibitors) may provide new strategies for treating pulmonary fibrosis and other organ fibrosis diseases. This study also lays the foundation for using CCL1/I-309 protein as a tool to further screen and validate novel drugs targeting this pathway.

V. Which Manufacturers Provide CCL1/I-309 Protein?

Nanjing UniAid Protein independently developed CCL1/I-309 Protein, Human (Catalog No.: UA040504), a high-purity, high-activity human CCL1 (also known as I-309) recombinant protein produced using a mammalian expression system, with spatial conformation and post-translational modifications consistent with the natural protein. CCL1 belongs to the CC chemokine family and primarily regulates T cell chemotaxis, immune modulation, and inflammatory responses by binding to the CCR8 receptor. This product is suitable for immune cell chemotaxis experiments, receptor binding studies, signaling pathway exploration, and drug screening, providing a reliable and efficient research tool.

Nanjing UniAid Protein is committed to providing high-quality core protein tools for immunology research, inflammatory model construction, and innovative drug development. For detailed technical parameters, activity validation data, or application inquiries regarding CCL1/I-309 Protein, Human (Catalog No.: UA040504), please feel free to contact us.