Inhibition of discoidin domain receptor 2 reveals kinase-dependent and kinase-independent functions in regulating fibroblast activity
Progressive pulmonary fibrosis is a devastating condition and current treatment is suboptimal. There has been considerable interest in the role of tyrosine kinase signaling as mediators of pro- and antifibrotic processes. Nintedanib is a nonspecific tyrosine kinase that has been shown to have therapeutic benefit in lung fibrosis. However, the precise mechanism of action remains unclear because nintedanib inhibits several tyrosine kinases, which are often expressed on multiple cell types with different activities during fibrosis. Discoidin domain receptor 2 (DDR2) has been suggested as a potential target of nintedanib. DDR2 is a receptor tyrosine kinase that is activated by fibrillar collagens such as type I collagen. DDR2 is primarily expressed by fibroblasts. The effectiveness of specifically targeting DDR2 signaling during fibrosis remains undefined. In the present study, we show that nintedanib acts as a direct and indirect inhibitor of DDR2. We then utilize a novel allosteric inhibitor of DDR2, WRG-28, which blocks ligand binding and activation of DDR2. We find that WRG-28 augments fibroblast apoptosis and attenuates fibrosis. Finally, we show that fibroblast type I collagen autocrine signaling is regulated by DDR2 through both kinase-dependent and kinase-independent functions of DDR2. These findings highlight the importance of type I collagen autocrine signaling by fibroblasts during fibrosis and demonstrate that DDR2 has a central role in this pathway making it a potential therapeutic target.NEW & NOTEWORTHY Type I collagen is a major component of fibrosis and can signal through cell surface receptors such as discoidin domain receptor 2 (DDR2). DDR2 activation can lead to further collagen deposition by fibroblasts setting up a profibrotic positive feedback loop. In this report, we find that inhibition of DDR2 with nintedanib or a specific DDR2 inhibitor, WRG-28, can disrupt this cycle and prevent fibrosis through augmented fibroblast apoptosis and inhibited activation.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2023 |
---|---|
Erschienen: |
2023 |
Enthalten in: |
Zur Gesamtaufnahme - volume:325 |
---|---|
Enthalten in: |
American journal of physiology. Lung cellular and molecular physiology - 325(2023), 3 vom: 01. Sept., Seite L342-L351 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Ling, Song [VerfasserIn] |
---|
Links: |
---|
Themen: |
Collagen |
---|
Anmerkungen: |
Date Completed 21.08.2023 Date Revised 07.11.2023 published: Print-Electronic figshare: 10.6084/m9.figshare.22193362 Citation Status MEDLINE |
---|
doi: |
10.1152/ajplung.00066.2023 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM359894836 |
---|
LEADER | 01000naa a22002652 4500 | ||
---|---|---|---|
001 | NLM359894836 | ||
003 | DE-627 | ||
005 | 20231226081841.0 | ||
007 | cr uuu---uuuuu | ||
008 | 231226s2023 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1152/ajplung.00066.2023 |2 doi | |
028 | 5 | 2 | |a pubmed24n1199.xml |
035 | |a (DE-627)NLM359894836 | ||
035 | |a (NLM)37489274 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Ling, Song |e verfasserin |4 aut | |
245 | 1 | 0 | |a Inhibition of discoidin domain receptor 2 reveals kinase-dependent and kinase-independent functions in regulating fibroblast activity |
264 | 1 | |c 2023 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 21.08.2023 | ||
500 | |a Date Revised 07.11.2023 | ||
500 | |a published: Print-Electronic | ||
500 | |a figshare: 10.6084/m9.figshare.22193362 | ||
500 | |a Citation Status MEDLINE | ||
520 | |a Progressive pulmonary fibrosis is a devastating condition and current treatment is suboptimal. There has been considerable interest in the role of tyrosine kinase signaling as mediators of pro- and antifibrotic processes. Nintedanib is a nonspecific tyrosine kinase that has been shown to have therapeutic benefit in lung fibrosis. However, the precise mechanism of action remains unclear because nintedanib inhibits several tyrosine kinases, which are often expressed on multiple cell types with different activities during fibrosis. Discoidin domain receptor 2 (DDR2) has been suggested as a potential target of nintedanib. DDR2 is a receptor tyrosine kinase that is activated by fibrillar collagens such as type I collagen. DDR2 is primarily expressed by fibroblasts. The effectiveness of specifically targeting DDR2 signaling during fibrosis remains undefined. In the present study, we show that nintedanib acts as a direct and indirect inhibitor of DDR2. We then utilize a novel allosteric inhibitor of DDR2, WRG-28, which blocks ligand binding and activation of DDR2. We find that WRG-28 augments fibroblast apoptosis and attenuates fibrosis. Finally, we show that fibroblast type I collagen autocrine signaling is regulated by DDR2 through both kinase-dependent and kinase-independent functions of DDR2. These findings highlight the importance of type I collagen autocrine signaling by fibroblasts during fibrosis and demonstrate that DDR2 has a central role in this pathway making it a potential therapeutic target.NEW & NOTEWORTHY Type I collagen is a major component of fibrosis and can signal through cell surface receptors such as discoidin domain receptor 2 (DDR2). DDR2 activation can lead to further collagen deposition by fibroblasts setting up a profibrotic positive feedback loop. In this report, we find that inhibition of DDR2 with nintedanib or a specific DDR2 inhibitor, WRG-28, can disrupt this cycle and prevent fibrosis through augmented fibroblast apoptosis and inhibited activation | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a Research Support, N.I.H., Extramural | |
650 | 4 | |a DDR2 | |
650 | 4 | |a collagen | |
650 | 4 | |a fibrosis | |
650 | 4 | |a matrix | |
650 | 7 | |a Discoidin Domain Receptor 2 |2 NLM | |
650 | 7 | |a EC 2.7.10.1 |2 NLM | |
650 | 7 | |a Collagen Type I |2 NLM | |
650 | 7 | |a Receptor Protein-Tyrosine Kinases |2 NLM | |
650 | 7 | |a EC 2.7.10.1 |2 NLM | |
700 | 1 | |a Kwak, Doyun |e verfasserin |4 aut | |
700 | 1 | |a Kim, Kevin K |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t American journal of physiology. Lung cellular and molecular physiology |d 2000 |g 325(2023), 3 vom: 01. Sept., Seite L342-L351 |w (DE-627)NLM105748501 |x 1522-1504 |7 nnns |
773 | 1 | 8 | |g volume:325 |g year:2023 |g number:3 |g day:01 |g month:09 |g pages:L342-L351 |
856 | 4 | 0 | |u http://dx.doi.org/10.1152/ajplung.00066.2023 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 325 |j 2023 |e 3 |b 01 |c 09 |h L342-L351 |