TNFSF10 drives hyperactive immune responses via NLRP3 inflammasome and endoplasmic reticulum stress in autoimmune and inflammatory diseases

• TNFSF10 is associated with autoimmune and inflammatory diseases, such as aplastic anemia (AA) • TNFSF10 induces inflammatory via activation of NF-κB pathway and NLRP3 inflammasome. • TNFSF10 impairs the recovery of hematopoiesis from ER stress via PPP1R15A. • TNFSF10 increases the exposure of CALR, thereby enhancing the “eat me” signaling from HSPCs. • AA-specific exosomes are assocaited with higher expression of TNFSF10 and ER stress. Autoimmune and inflammatory diseases are characterized by multifaceted pathogenesis, demanding effective therapeutic strategies. TNFSF10 is typically regarded as a pro-apoptotic ligand, yet its functions under physiological and pathological conditions remain elusive. scRNA-seq analysis of immune cells from patients with aplastic anemia (AA) was performed to identify the crucial DEGs,with TNFSF10 being highlighted as a key regulator. Tnfsf10-deficient mice were used to establish an AA mouse model, and other mouse models, such as ER stress, aGVHD, radiation-induced aging, and IBD, which facilitated the exploration of the biological function of TNFSF10. Here, we show that TNFSF10 contributes to the imbalance of immune homeostasis and immunogenic cell death (ICD) under pathological circumstances. The ICD-provoking effect and proinflammatory property of TNFSF10 is associated with the activation of the NF-κB pathway and NLRP3 inflammasome. Additionally, TNFSF10 is a crucial amplifier of endoplasmic reticulum stress by enhancing the expression of PPP1R15A, thereby contributing to NLRP3 inflammasome activation. Moreover, TNFSF10-associated ER stress is a driver of surface Calreticulin (CALR) exposure, which transmits an “eat me” signal to hyperactivated immune cells and accelerates the clearance of hematopoietic cells. We also found that AA-specific exosomes may contribute to ER stress and the expression of TNFSF10. Collectively, our study reveals the key role of TNFSF10 in autoimmune and inflammatory diseases, integrating the NF-κB, NLRP3 inflammasome, and ER stress pathways, and further accelerating the disease process.