TY - JOUR TI - D-dopachrome tautomerase contributes to lung epithelial repair via atypical chemokine receptor 3-dependent Akt signaling AU - Song, Shanshan AU - Liu, Bin AU - Habibie, Habibie AU - Bor, Jelle van den AU - Smit, Martine J. AU - Gosens, Reinoud AU - Wu, Xinhui AU - Brandsma, Corry-Anke AU - Cool, Robbert H. AU - Haisma, Hidde J. AU - Poelarends, Gerrit J. AU - Melgert, Barbro N. T2 - EBioMedicine AB -

Abstract

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.

DA - 2021/06/01/ PY - 2021 DO - 10.1016/j.ebiom.2021.103412 DP - www.thelancet.com VL - 68 J2 - EBioMedicine LA - English SN - 2352-3964 UR - https://www.thelancet.com/journals/ebiom/article/PIIS2352-3964(21)00205-X/abstract Y2 - 2021/06/10/18:23:41 ER -