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Editor’s note iNature is China’s largest academic official account.
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
iNature pulmonary fibrosis (PF) is the pathological basis of many fibroproliferative lung diseases and an independent chronic disease, namely idiopathic PF (IPF)
.
Effective anti-PF therapy remains an urgent and unmet medical need
.
Therefore, a better understanding of the molecular and cellular mechanisms of PF is essential for the discovery of effective anti-PF drugs
.
The recruitment of immune cells to the site of inflammation by the chemokine CCL1 is important in the pathology of inflammatory diseases
.
On August 17, 2021, Central South University Hu Zhuowei and Xiao Yang jointly published a research paper entitled "The chemokine CCL1 triggers an AMFR-SPRY1 pathway that promotes differentiation of lung fibroblasts into myofibroblasts and drives pulmonary fibrosis" in Immunity.
The role of CCL1 in pulmonary fibrosis (PF) is described
.
The bronchoalveolar lavage fluid from the PF mouse model contains a large amount of CCL1, as is the lung biopsy from PF patients
.
Immunofluorescence analysis showed that alveolar macrophages and CD4+ T cells are the main producers of CCL1, and the targeted deletion of Ccl1 in these cells blunts the pathology
.
The absence of CCL1 receptor Ccr8 in fibroblasts limits the migration of CCL1, but does not limit its activation
.
Mass spectrometry analysis of the CCL1 complex identified AMFR as a CCL1 receptor, and the absence of Amfr would impair the activation of fibroblasts
.
Mechanistically speaking, CCL1 binding triggers AMFR's ubiquitination of the ERK inhibitor Spry1, thereby activating Ras-mediated synthesis of pro-fibrotic proteins
.
Antibody blockade of CCL1 improves the pathology of PF and supports the therapeutic potential of targeting this pathway to treat fibroproliferative lung disease
.
Pulmonary fibrosis (PF) is the pathological basis of many fibroproliferative lung diseases and an independent chronic disease, namely idiopathic PF (IPF)
.
Effective anti-PF therapy remains an urgent and unmet medical need
.
Therefore, a better understanding of the molecular and cellular mechanisms of PF is essential for the discovery of effective anti-PF drugs
.
Different types of lung cells contribute to fibrosis, which is a sign of PF
.
Myofibroblasts are important effector cells of PF because they produce large amounts of extracellular matrix (ECM) in the alveoli and interstitium
.
Under the stimulation of various cytokines and growth factors released by alveolar epithelial cells and immune cells, myofibroblasts differentiated from lung fibroblasts and bone marrow-derived fibroblasts
.
For example, the enhancement of CCL2 produced by alveolar epithelial cells (AEC) in patients with IPF can directly induce fibroblasts to differentiate into α-smooth muscle actin (α-SMA)-positive myofibroblasts
.
Among immune cells, macrophages are close to activated myofibroblasts and cause chronic inflammation of lung tissue
.
During PF, alveolar macrophages (AMs) secrete elevated levels of the chemokine CCL18, which directly activates lung fibroblasts and stimulates collagen production
.
It is important to identify the mediators released by various immune cells (such as AM) that contribute to the activation of myofibroblasts and subsequent fibrosis during the development of PF
.
Article pattern (picture from Immunity) Chemokines are a type of cytokines that are locally expressed in inflammation sites and can regulate the recruitment of leukocytes and lymphocytes to damaged tissues
.
Generally, chemokines induce biological activity by activating G protein-coupled chemokine receptors
.
Most chemokine receptors recognize more than one chemokine, and many chemokines bind to more than one receptor
.
Chemokines (CC motif) ligand 1 (CCL1) recruits immune cells to injury sites and inflammatory tissues through interaction with its receptor CCR8, thereby regulating tissue homeostasis
.
In this way, CCL1 and CCR8 can cause various human inflammatory diseases
.
For example, CCL1 recruits T cells and Langerhans-type dendritic cells in atopic dermatitis
.
The CCL1-CCR8 interaction promotes the recruitment of lymphocytes in immunoglobulin G4 (IgG4)-related sclerosing cholangitis, leading to catheter-centric inflammation and phlebitis obliterans
.
Therefore, CCL1 is involved in the pathological process of inflammatory diseases
.
Given that tissue fibrosis is also a chronic inflammatory disease, this study sought to determine the effect of CCL1 on the development of tissue fibrosis in the context of PF
.
The study found that CCL1 was elevated in bronchoalveolar lavage fluid (BALF) from PF mice and human fibrotic lung tissues, supporting the role of CCL1 in the development of PF
.
In addition, the enhanced expression of CCL1 by immune cells interacts with the autocrine motility factor receptor (AMFR) in the fibrotic lung tissues of PF patients and PF mouse models, activating lung fibroblasts into myofibroblasts, thereby promoting Fibrosis
.
Mechanistically speaking, CCL1 triggers AMFR phosphorylation, which activates the E3 ligase activity of AMFR and the downstream ubiquitination of the ERK inhibitor Spry1
.
This alleviates the inhibitory effect of Spry1 on ERK-p70S6K signaling activity and enhances the synthesis of pro-fibrotic proteins
.
The results of this study use the CCL1-AMFR-ERK signaling cascade as a therapeutic target for the treatment of PF
.
Reference message: https://#%20
It is jointly created by the doctoral team of Tsinghua University, Harvard University, Chinese Academy of Sciences and other units.
The iNature Talent Official Account is now launched, focusing on talent recruitment, academic progress, scientific research information, interested parties can Long press or scan the QR code below to follow us
.
iNature pulmonary fibrosis (PF) is the pathological basis of many fibroproliferative lung diseases and an independent chronic disease, namely idiopathic PF (IPF)
.
Effective anti-PF therapy remains an urgent and unmet medical need
.
Therefore, a better understanding of the molecular and cellular mechanisms of PF is essential for the discovery of effective anti-PF drugs
.
The recruitment of immune cells to the site of inflammation by the chemokine CCL1 is important in the pathology of inflammatory diseases
.
On August 17, 2021, Central South University Hu Zhuowei and Xiao Yang jointly published a research paper entitled "The chemokine CCL1 triggers an AMFR-SPRY1 pathway that promotes differentiation of lung fibroblasts into myofibroblasts and drives pulmonary fibrosis" in Immunity.
The role of CCL1 in pulmonary fibrosis (PF) is described
.
The bronchoalveolar lavage fluid from the PF mouse model contains a large amount of CCL1, as is the lung biopsy from PF patients
.
Immunofluorescence analysis showed that alveolar macrophages and CD4+ T cells are the main producers of CCL1, and the targeted deletion of Ccl1 in these cells blunts the pathology
.
The absence of CCL1 receptor Ccr8 in fibroblasts limits the migration of CCL1, but does not limit its activation
.
Mass spectrometry analysis of the CCL1 complex identified AMFR as a CCL1 receptor, and the absence of Amfr would impair the activation of fibroblasts
.
Mechanistically speaking, CCL1 binding triggers AMFR's ubiquitination of the ERK inhibitor Spry1, thereby activating Ras-mediated synthesis of pro-fibrotic proteins
.
Antibody blockade of CCL1 improves the pathology of PF and supports the therapeutic potential of targeting this pathway to treat fibroproliferative lung disease
.
Pulmonary fibrosis (PF) is the pathological basis of many fibroproliferative lung diseases and an independent chronic disease, namely idiopathic PF (IPF)
.
Effective anti-PF therapy remains an urgent and unmet medical need
.
Therefore, a better understanding of the molecular and cellular mechanisms of PF is essential for the discovery of effective anti-PF drugs
.
Different types of lung cells contribute to fibrosis, which is a sign of PF
.
Myofibroblasts are important effector cells of PF because they produce large amounts of extracellular matrix (ECM) in the alveoli and interstitium
.
Under the stimulation of various cytokines and growth factors released by alveolar epithelial cells and immune cells, myofibroblasts differentiated from lung fibroblasts and bone marrow-derived fibroblasts
.
For example, the enhancement of CCL2 produced by alveolar epithelial cells (AEC) in patients with IPF can directly induce fibroblasts to differentiate into α-smooth muscle actin (α-SMA)-positive myofibroblasts
.
Among immune cells, macrophages are close to activated myofibroblasts and cause chronic inflammation of lung tissue
.
During PF, alveolar macrophages (AMs) secrete elevated levels of the chemokine CCL18, which directly activates lung fibroblasts and stimulates collagen production
.
It is important to identify the mediators released by various immune cells (such as AM) that contribute to the activation of myofibroblasts and subsequent fibrosis during the development of PF
.
Article pattern (picture from Immunity) Chemokines are a type of cytokines that are locally expressed in inflammation sites and can regulate the recruitment of leukocytes and lymphocytes to damaged tissues
.
Generally, chemokines induce biological activity by activating G protein-coupled chemokine receptors
.
Most chemokine receptors recognize more than one chemokine, and many chemokines bind to more than one receptor
.
Chemokines (CC motif) ligand 1 (CCL1) recruits immune cells to injury sites and inflammatory tissues through interaction with its receptor CCR8, thereby regulating tissue homeostasis
.
In this way, CCL1 and CCR8 can cause various human inflammatory diseases
.
For example, CCL1 recruits T cells and Langerhans-type dendritic cells in atopic dermatitis
.
The CCL1-CCR8 interaction promotes the recruitment of lymphocytes in immunoglobulin G4 (IgG4)-related sclerosing cholangitis, leading to catheter-centric inflammation and phlebitis obliterans
.
Therefore, CCL1 is involved in the pathological process of inflammatory diseases
.
Given that tissue fibrosis is also a chronic inflammatory disease, this study sought to determine the effect of CCL1 on the development of tissue fibrosis in the context of PF
.
The study found that CCL1 was elevated in bronchoalveolar lavage fluid (BALF) from PF mice and human fibrotic lung tissues, supporting the role of CCL1 in the development of PF
.
In addition, the enhanced expression of CCL1 by immune cells interacts with the autocrine motility factor receptor (AMFR) in the fibrotic lung tissues of PF patients and PF mouse models, activating lung fibroblasts into myofibroblasts, thereby promoting Fibrosis
.
Mechanistically speaking, CCL1 triggers AMFR phosphorylation, which activates the E3 ligase activity of AMFR and the downstream ubiquitination of the ERK inhibitor Spry1
.
This alleviates the inhibitory effect of Spry1 on ERK-p70S6K signaling activity and enhances the synthesis of pro-fibrotic proteins
.
The results of this study use the CCL1-AMFR-ERK signaling cascade as a therapeutic target for the treatment of PF
.
Reference message: https://#%20
