Long non-coding RNA H19 contributes to M1 macrophage polarization mediated inflammation via miR-145-5p-PAI-1 axis in systemic lupus erythematosus.

Abstract

Systemic lupus erythematosus (SLE) represents a prototypical autoimmune disorder characterized by multi-organ involvement due to loss of immune tolerance. Emerging evidence implicates macrophage polarization dynamics as a pivotal contributor to SLE pathogenesis, with epigenetic regulation by long noncoding RNAs (lncRNAs) emerging as a critical regulatory mechanism. To elucidate the pathogenic role of exosome-derived lncRNAs in this process, we performed comprehensive RNA sequencing analysis on circulating exosomes from SLE patients, identifying lncRNA H19 as a significantly upregulated candidate. Subsequent functional analyses using primary murine macrophages demonstrated that exogenous H19 administration recapitulated the pro-inflammatory phenotype observed in SLE, as evidenced by enhanced M1 macrophage differentiation, transmigration capacity, and renal infiltration patterns in experimental models. Notably, we primarily identified lncRNA H19 as a potential indicator in SLE, the knockdown of which might significantly attenuate these pathological manifestations. Mechanistic investigations revealed that H19 promoted the proliferation and migration of macrophages in vitro and exerted its regulatory function through competitive binding to miR-145-5p, thereby derepressing PAI-1 expression and subsequently activating the JAK2-STAT3 signaling cascade to orchestrate pro-inflammatory cytokine production. Overall, this study reveals novel molecular mechanisms underlying immune dysregulation in SLE, establishing exosomal lncRNA H19 as a key epigenetic modulator of macrophage polarization via the miR-145-5p/PAI-1/STAT3 axis, and proposes a novel potential therapeutic target for restoring immune homeostasis in patients with SLE before clinical practice.