Autologous chylous fat improves hypertrophic scars via TSG-6: association with endoplasmic reticulum stress mediated by IRE1α phosphorylation and JNK activation.

Abstract

Hypertrophic scars (HS) represent pathological outcomes of traumatic or surgical injuries with dysregulated wound healing. We investigated the therapeutic effects and underlying mechanism of autologous chyle fat (ALCF) in HS formation. A thermal injury-induced burn wound model was established in mice. Histopathological alterations, fibrotic deposition, the levels of α-smooth muscle actin (α-SMA), collagen I and collagen III were quantified. To elucidate the mechanism, tumor necrosis factor-stimulated gene-6 (TSG-6) was silenced, and TSG-6, binding immunoglobulin protein (Bip), C/EBP homologous protein (CHOP), inositol-requiring enzyme 1α (IRE1α), p-IRE1α, c-Jun N-terminal kinase (JNK), and p-JNK were assessed to evaluate endoplasmic reticulum stress (ERS) and downstream signaling. The JNK signaling pathway was pharmacologically activated to validate the IRE1α/JNK axis. Clinically, ALCF injection yielded favorable outcomes. ALCF markedly alleviated fibrosis in burn wound scar tissues and reduced Bip and CHOP, indicating ERS attenuation. ALCF upregulated TSG-6 expression in healing wound tissues, whereas TSG-6 knockdown partially abolished the antifibrotic effects of ALCF. ALCF suppressed IRE1α phosphorylation and JNK activation. Reactivation of the IRE1α/JNK pathway reversed the inhibitory effects of ALCF on ERS and promoted fibrotic deposition. Collectively, ALCF attenuates burn wound fibrosis through TSG-6-mediated suppression of ERS, associated with reduced IRE1α phosphorylation and JNK signaling inhibition.