Intercellular communication plays an essential role in lung cancer (LC). One of the major players in cell‐cell‐communication is small extracellular vesicles (sEV). SEV trigger various biological responses by transporting cellular cargo to target cells. One essential sEV component are microRNAs (miRs), whose transport has recently attracted increasing research interest. We report that prostaglandin E 2 (PGE 2 ), a key inflammatory lipid mediator, specifically induces the sorting of miR‐574‐5p in sEV of A549 and 2106T cells. We found that sEV‐derived miR‐574‐5p activates Toll‐like receptors (TLR) 7/8, thereby decreasing PGE 2 ‐levels. In contrast, intracellular miR‐574‐5p induces PGE 2 ‐biosynthesis. Consequently, the combination of intracellular and sEV‐derived miR‐574‐5p controls PGE 2 ‐levels via a feedback loop. This was only observed in adeno‐ but not in squamous cell carcinoma, indicating a cell‐specific response to sEV‐derived miRs, which might be due to unique tetraspanin compositions. Hence, we describe a novel function of miR‐574‐5p unique to adenocarcinoma. Intracellular miR‐574‐5p induces PGE 2 and thus the secretion of sEV‐derived miR‐574‐5p, which in turn decreases PGE 2 ‐biosynthesis in recipient cells.

Stabilin‐1 (Stab1) and Stabilin‐2 (Stab2) are two major scavenger receptors of liver sinusoidal endothelial cells that mediate removal of diverse molecules from the plasma. Double‐knockout mice (Stab‐DKO) develop impaired kidney function and a decreased lifespan, while single Stabilin deficiency or therapeutic inhibition ameliorates atherosclerosis and Stab1‐inhibition is subject of clinical trials in immuno‐oncology. Although POSTN and TFGBI have recently been described as novel Stabilin ligands, the dynamics and functional implications of these ligands have not been comprehensively studied. Immunofluorescence, Western Blotting and Simple Western™ as well as in situ hybridization (RNAScope™) and qRT‐PCR were used to analyze transcription levels and tissue distribution of POSTN and TGFBI in Stab‐KO mice. Stab‐POSTN‐Triple deficient mice were generated to assess kidney and liver fibrosis and function in young and aged mice. TGFBI and POSTN protein accumulated in liver tissue in Stab‐DKO mice and age‐dependent in glomeruli of Stabilin‐deficient mice despite unchanged transcriptional levels. Stab‐POSTN‐Triple KO mice showed glomerulofibrosis and a reduced lifespan comparable to Stab‐DKO mice. However, alterations of the glomerular diameter and vascular density were partially normalized in Stab‐POSTN‐Triple KO. TGFBI and POSTN are Stabilin‐ligands that are deposited in an age‐dependent manner in the kidneys and liver due to insufficient scavenging in the liver. Functionally, POSTN might partially contribute to the observed renal phenotype in Stab‐DKO mice. This study provides details on downstream effects how Stabilin dysfunction affects organ function on a molecular and functional level.

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Liver sinusoidal endothelial cells (LSECs) control clearance of Transforming growth factor, beta-induced, 68kDa (TGFBi) and Periostin (POSTN) through scavenger receptors Stabilin-1 (Stab1) and Stabilin-2 (Stab2). Stabilin inhibition can ameliorate atherosclerosis in mouse models, while Stabilin-double-knockout leads to glomerulofibrosis. Fibrotic organ damage may pose a limiting factor in future anti-Stabilin therapies. While Stab1-deficient (Stab1−/−) mice were shown to exhibit higher liver fibrosis levels upon challenges, fibrosis susceptibility has not been studied in Stab2-deficient (Stab2−/−) mice. Wildtype (WT), Stab1−/− and Stab2−/− mice were fed experimental diets, and local ligand abundance, hepatic fibrosis, and ligand plasma levels were measured. Hepatic fibrosis was increased in both Stab1−/− and Stab2−/− at baseline. A pro-fibrotic short Methionine-Choline-deficient (MCD) diet induced slightly increased liver fibrosis in Stab1−/− and Stab2−/− mice. A Choline-deficient L-amino acid-defined (CDAA) diet induced liver fibrosis of similar distribution and extent in all genotypes (WT, Stab1−/− and Stab2−/−). A hepatic abundance of Stabilin ligand TGFBi correlated very highly with liver fibrosis levels. In contrast, plasma levels of TGFBi were increased only in Stab2−/− mice after the CDAA diet but not the MCD diet, indicating the differential effects of these diets. Here we show that a single Stabilin deficiency of either Stab1 or Stab2 induces mildly increased collagen depositions under homeostatic conditions. Upon experimental dietary challenge, the local abundance of Stabilin ligand TGFBi was differentially altered in Stabilin-deficient mice, indicating differentially affected LSEC scavenger functions. Since anti-Stabilin-directed therapies are in clinical evaluation for the treatment of diseases, these findings bear relevance to treatment with novel anti-Stabilin agents.

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