D-dopachrome tautomerase contributes to lung epithelial repair via atypical chemokine receptor 3-dependent Akt signaling
Shanshan Song,
Bin Liu,
Habibie Habibie,
Jelle van den Bor,
Martine J. Smit,
Reinoud Gosens,
Xinhui Wu,
Corry-Anke Brandsma,
Robbert H. Cool,
Hidde J. Haisma,
Gerrit J. Poelarends,
Barbro N. Melgert
Affiliations
Shanshan Song
Groningen Research Institute of Pharmacy, Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands; Groningen Research Institute of Pharmacy, Department of Chemical and Pharmaceutical Biology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands
Bin Liu
Groningen Research Institute of Pharmacy, Department of Chemical and Pharmaceutical Biology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands
Habibie Habibie
Groningen Research Institute of Pharmacy, Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands; University Medical Center Groningen, Groningen Research Institute of Asthma and COPD, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands; Faculty of Pharmacy, Hasanuddin University, Makassar 90245, Indonesia
Jelle van den Bor
Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands
Martine J. Smit
Division of Medicinal Chemistry, Amsterdam Institute of Molecular and Life Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1108, 1081 HZ Amsterdam, the Netherlands
Reinoud Gosens
Groningen Research Institute of Pharmacy, Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands; University Medical Center Groningen, Groningen Research Institute of Asthma and COPD, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands
Xinhui Wu
Groningen Research Institute of Pharmacy, Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands; University Medical Center Groningen, Groningen Research Institute of Asthma and COPD, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands
Corry-Anke Brandsma
University Medical Center Groningen, Groningen Research Institute of Asthma and COPD, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands; University Medical Center Groningen, Department of Pathology and Medical Biology, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands
Robbert H. Cool
Groningen Research Institute of Pharmacy, Department of Chemical and Pharmaceutical Biology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands
Hidde J. Haisma
Groningen Research Institute of Pharmacy, Department of Chemical and Pharmaceutical Biology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands
Gerrit J. Poelarends
Groningen Research Institute of Pharmacy, Department of Chemical and Pharmaceutical Biology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands
Barbro N. Melgert
Groningen Research Institute of Pharmacy, Department of Molecular Pharmacology, University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, the Netherlands; University Medical Center Groningen, Groningen Research Institute of Asthma and COPD, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands; Corresponding author.
Background: Emphysematous COPD is characterized by aberrant alveolar repair. Macrophage migration inhibitory factor (MIF) contributes to alveolar repair, but for its structural and functional homolog D-dopachrome tautomerase (DDT) this is unknown. MIF mediates its effects through CD74 and/or C-X-C chemokine receptors 2 (CXCR2), 4(CXCR4), and possibly 7 (ACKR3). DDT can also signal through CD74, but interactions with other receptors have not been described yet. We therefore aimed at investigating if and how DDT contributes to epithelial repair in COPD. Methods: We studied effects of recombinant DDT on cell proliferation and survival by clonogenic assay and annexin V-PI staining respectively. DDT-induced signaling was investigated by Western blot. Effects on epithelial growth and differentiation was studied using lung organoid cultures with primary murine or human epithelial cells and incubating with DDT or an ACKR3-blocking nanobody. DDT-ACKR3 interactions were identified by ELISA and co-immunoprecipitation. Findings: We found that DDT promoted proliferation of and prevented staurosporine-induced apoptosis in A549 lung epithelial cells. Importantly, DDT also stimulated growth of primary alveolar epithelial cells as DDT treatment resulted in significantly more and larger murine and human alveolar organoids compared to untreated controls. The anti-apoptotic effect of DDT and DDT-induced organoid growth were inhibited in the presence of an ACKR3-blocking nanobody. Furthermore, ELISA assay and co-immunoprecipitation suggested DDT complexes with ACKR3. DDT could activate the PI3K-Akt pathway and this activation was enhanced in ACKR3-overexpressing cells. Interpretation: In conclusion, DDT contributes to alveolar epithelial repair via ACKR3 and may thus augment lung epithelial repair in COPD. Funding: As stated in the Acknowledgments.
