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. 2025 Jun 19;65(6):2400003.
doi: 10.1183/13993003.00003-2024. Print 2025 Jun.

Mannose-6-phosphate attenuates acute lung injury by competitive release of acid sphingomyelinase from the mannose-6-phosphate receptor in endothelial caveolae

Tian Jiang  1   2 , Rudi Samapati  1 , Sergej Klassen  3 , Supandi Winoto-Morbach  4 , Zain H Mohamed  5 , Rolf Göggel  6 , Jun Yin  2 , Lijie Tan  2 , Christoph Arenz  5 , Sabrina Schulz  1 , Lasti Erfinanda  1 , Robert Preissner  1 , Szandor Simmons  1 , Stefan Schütze  4 , Stefan Uhlig  3   7 , Wolfgang M Kuebler  8   9   10   7
Affiliations

Mannose-6-phosphate attenuates acute lung injury by competitive release of acid sphingomyelinase from the mannose-6-phosphate receptor in endothelial caveolae

Tian Jiang et al. Eur Respir J. .

Abstract

Background: Platelet-activating factor (PAF)-induced pulmonary endothelial barrier failure is mediated by acid sphingomyelinase (ASM) translocation to caveolae. ASM, however, lacks a transmembrane domain for anchoring inside caveolae. We hypothesised that ASM anchors to cation-independent mannose-6-phosphate (M6P) receptor (CI-M6PR) in caveolae, from where it can be competitively released by M6P.

Methods: We explored ASM-CI-M6PR interactions using co-immunoprecipitation and proximity ligation assay in isolated lungs and human pulmonary microvascular endothelial cells. ASM release by M6P was determined in human pulmonary microvascular endothelial cells, isolated lungs and in vivo. The effects of M6P on 1) PAF-induced lung oedema formation and endothelial Ca2+ concentration and 2) lung injury in acid instilled, overventilated mouse lungs were examined. ASM levels were measured in serum and bronchoalveolar lavage fluid of patients with acute respiratory distress syndrome. The TriNetX database was probed for associations of ASM-inhibiting tricyclic antidepressants with outcomes.

Results: Co-immunoprecipitation and proximity ligation assay revealed an ASM interaction with CI-M6PR in endothelial caveolae, which was further increased by PAF. M6P, but not glucose-6-phosphate, caused ASM release, thereby decreasing ASM content and activity in caveolae in vitro, in situ and in vivo. Analogously, M6P, yet not glucose-6-phosphate, attenuated PAF-induced endothelial Ca2+ influx and lung oedema in situ, and acute lung injury in vivo. ASM levels were increased in serum but not bronchoalveolar lavage fluid in patients with acute respiratory distress syndrome. Use of tricyclic antidepressants was associated with better outcomes in patients with severe respiratory infections.

Conclusions: CI-M6PR anchors ASM in caveolae. M6P may hence present a promising target in ASM-related lung injury and oedema.

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Conflict of interest statement

Conflict of interest: S. Schütze reports support for the present manuscript from Deutsche Forschungsgemeinschaft (SCHU733/14-1, SFP 877 (B1)). S. Uhlig reports support for the present manuscript from German Research Foundation (DFG UH 88/9-1, SFB 367 TP A09). W.M. Kuebler reports support for the present study from the German Research Foundation (DFG), German Ministry of Education and Research (BMBF) and German Centre for Cardiovascular Research (DZHK); grants from SPARK BIH Validation Fund; patents planned, issued or pending including International Patent File PCT/EP 97/04725 (1997), European Patent File Number 08016142.5, International Patent File PCT/EP2012/065639, German Patent application Number CH937/2019, European Patent application number 20196830.2 – 1112, European Patent application number EP21205486.0 and European Patent application number EP 22162072.7; participation on a data safety monitoring board or advisory board with the Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria; and a leadership role with the Publications Committee of the American Physiological Society. The remaining authors have no potential conflicts of interest to disclose.

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