Abstract / Summary
Introduction: Autoimmune and inflammatory diseases are characterized by multifaceted pathogenesis, demanding effective therapeutic strategies. Objectives: TNFSF10 is typically regarded as a pro-apoptotic ligand, yet its functions under physiological and pathological conditions remain elusive. Methods: 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. Results: 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. Conclusion: 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.