ETS1 activates heparanase transcription to drive intra-islet heparan sulfate degradation and macrophage-induced insulitis in type 1 diabetes

The infiltration of pro-inflammatory macrophages and the enzymatic degradation of the protective intra-islet heparan sulfate (HS) barrier are established pathological hallmarks of type 1 diabetes (T1D). While we previously identified myeloid-derived heparanase (HPSE) as the primary enzyme responsible for intra-islet HS cleavage, the transcriptional mechanisms driving its aberrant upregulation in macrophages remain unknown. By integrating single-cell RNA sequencing of T1D immune cells, we identified the transcription factor ETS proto-oncogene 1 (ETS1) as a key upstream regulator of Hpse in T1D-specific macrophages. Mechanistically, Cleavage Under Targets and Tagmentation (CUT&Tag) and luciferase reporter assays confirmed that ETS1 directly binds to the Hpse promoter and activates its expression in macrophages. In vivo, myeloid-specific Ets1 knockout (Ets1-mKO) mice exhibited profound resistance to multiple low-dose streptozotocin (MLD-STZ)-induced T1D insulitis. This protection was driven by the marked suppression of myeloid HPSE expression, which preserved intra-islet HS levels, reduced inflammatory cell infiltration, and enhanced β-cell survival compared with that in wild-type littermates. In conclusion, our findings define a previously unrecognized ETS1-HPSE-HS signaling axis that is involved in macrophage-mediated islet damage in T1D. We demonstrate that ETS1 is a crucial driver of the enzymatic breakdown of the islet basement membrane and the subsequent progression of insulitis, suggesting that targeting the ETS1-mediated transcriptional activation of HPSE offers a novel therapeutic strategy to safeguard the islet microenvironment and slow the progression of T1D.