The interplay of type I interferon, NLRP3 inflammasome, and self-antigen clearance in systemic lupus erythematosus progression
DOI:
https://doi.org/10.35335/midwifery.v14i1.2317Keywords:
Autoimmune, Disease Progression, IFN-1, Inflammatory Pathway, NLRP3 Inflammasome, SLEAbstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease driven by impaired cellular debris clearance. While individual inflammatory pathways are well-documented, their synergistic interactions lack comprehensive synthesis, hindering the development of mechanism-based therapeutics. This literature review aims to elucidate the interconnected roles of specific cellular inflammatory pathways and their positive feedback loops in driving the clinical progression of SLE. A comprehensive literature review was conducted by analyzing 35 peer-reviewed scientific studies published between 2015 and 2025, sourced primarily from the PubMed database, focusing on SLE pathogenesis, cellular inflammation, and disease severity. SLE progression is propelled by a mutually reinforcing inflammatory cascade rather than isolated pathways. We identified three primary components establishing a pathological positive feedback loop: (1) Impaired self-antigen clearance, supplying a continuous source of Damage-Associated Molecular Patterns (DAMPs); (2) Type I Interferon (IFN-I) overactivation, acting as the systemic immune response conductor; and (3) The NLRP3 inflammasome, functioning as a local amplifier that induces direct tissue damage. The identification of this synergistic feedback loop demonstrates that single-target interventions may be insufficient. Comprehending this dynamic cascade necessitates a paradigm shift towards precision medicine. Future therapeutic strategies must prioritize multi-target combination therapies, stratifying patients based on their unique biological profiles to disrupt the pathogenic cycle effectively.
Downloads
References
Arnaud, L., Chasset, F., & Martin, T. (2024). Immunopathogenesis of systemic lupus erythematosus: An update. Autoimmunity Reviews, 23(10), 103648. https://doi.org/10.1016/J.AUTREV.2024.103648
Arneth, B. (2019). Systemic Lupus Erythematosus and DNA Degradation and Elimination Defects. Frontiers in Immunology, 10. https://doi.org/10.3389/fimmu.2019.01697
Chang, L. (2024). Harnessing cGAS–STING axis for therapeutic benefits in systemic lupus erythematosus. International Journal of Rheumatic Diseases, 27(7). https://doi.org/10.1111/1756-185X.15256
Chen, F., Liu, X., Tao, J., Mao, Z., Wang, H., Tan, Y., Qu, Z., & Yu, F. (2023). Renal NLRP3 Inflammasome activation is associated with disease activity in lupus nephritis. Clinical Immunology, 247, 109221. https://doi.org/10.1016/j.clim.2022.109221
Chyuan, I.-T., Tzeng, H.-T., & Chen, J.-Y. (2019). Signaling Pathways of Type I and Type III Interferons and Targeted Therapies in Systemic Lupus Erythematosus. Cells, 8(9), 963. https://doi.org/10.3390/cells8090963
Cranford, S. W. (2020). Seven Seconds or Less: Buzzwordy Titles in the Era of MOFs and Tinder. Matter, 3(4), 965–967.
Dai, X., Fan, Y., & Zhao, X. (2025). Systemic lupus erythematosus: updated insights on the pathogenesis, diagnosis, prevention and therapeutics. Signal Transduction and Targeted Therapy, 10(1), 102. https://doi.org/10.1038/s41392-025-02168-0
Fetter, T., de Graaf, D. M., Claus, I., & Wenzel, J. (2023). Aberrant inflammasome activation as a driving force of human autoimmune skin disease. Frontiers in Immunology, 14. https://doi.org/10.3389/fimmu.2023.1190388
Gómez-Bañuelos, E., Goldman, D. W., Andrade, V., Darrah, E., Petri, M., & Andrade, F. (2024). Uncoupling interferons and the interferon signature explains clinical and transcriptional subsets in SLE. Cell Reports Medicine, 5(5), 101569. https://doi.org/10.1016/j.xcrm.2024.101569
Grieshaber, S. (2020). Equity and research design. In Doing early childhood research (pp. 177–191). Routledge.
Gu, X., Chen, Y., Cao, K., Tu, M., Liu, W., & Ju, J. (2024). Therapeutic landscape in systemic lupus erythematosus: mtDNA activation of the cGAS-STING pathway. International Immunopharmacology, 133, 112114. https://doi.org/10.1016/j.intimp.2024.112114
Guan, X., He, X., & Liu, L. (2025). Neutrophil extracellular traps and neuropsychiatric lupus: Signaling pathways involved in NET formation and mechanisms affecting the central nervous system. Autoimmunity Reviews, 24(11), 103897. https://doi.org/10.1016/j.autrev.2025.103897
Gupta, S., & Kaplan, M. J. (2021). Bite of the wolf: innate immune responses propagate autoimmunity in lupus. Journal of Clinical Investigation, 131(3). https://doi.org/10.1172/JCI144918
Holers, V. M. (2025). Systemic lupus erythematosus as the paradigm for understanding the complex immune relationships and therapeutic opportunities for targeting complement in autoimmune diseases. Immunobiology, 230(3), 152915. https://doi.org/10.1016/j.imbio.2025.152915
Ji, L., Li, T., Chen, H., Yang, Y., Lu, E., Liu, J., Qiao, W., & Chen, H. (2023). The crucial regulatory role of type I interferon in inflammatory diseases. Cell & Bioscience, 13(1), 230. https://doi.org/10.1186/s13578-023-01188-z
Jones, S. A., & Morand, E. F. (2024). Targeting Interferon Signalling in Systemic Lupus Erythematosus: Lessons Learned. Drugs, 84(6), 625–635. https://doi.org/10.1007/s40265-024-02043-2
Justiz Vaillant, A. A., Goyal, A., & Varacallo, M. A. (2025). Systemic Lupus Erythematosus.
Kalliolias, G. D., Basdra, E. K., & Papavassiliou, A. G. (2024). Targeting TLR Signaling Cascades in Systemic Lupus Erythematosus and Rheumatoid Arthritis: An Update. Biomedicines, 12(1). https://doi.org/10.3390/biomedicines12010138
Lai, B., Luo, S.-F., & Lai, J.-H. (2024). Therapeutically targeting proinflammatory type I interferons in systemic lupus erythematosus: efficacy and insufficiency with a specific focus on lupus nephritis. Frontiers in Immunology, 15. https://doi.org/10.3389/fimmu.2024.1489205
Londe, A. C., Fernandez-Ruiz, R., Julio, P. R., Appenzeller, S., & Niewold, T. B. (2023). Type I Interferons in Autoimmunity: Implications in Clinical Phenotypes and Treatment Response. The Journal of Rheumatology, 50(9), 1103–1113. https://doi.org/10.3899/jrheum.2022-0827
Luo, H., Tian, T., Hu, C., & Hao, F. (2025). Targeting the cGAS-STING pathway: emerging strategies and challenges for the treatment of inflammatory skin diseases. Frontiers in Pharmacology, 16, 1597443. https://doi.org/10.3389/fphar.2025.1597443
Ma, Z.-Z., Sun, H.-S., Lv, J.-C., Guo, L., & Yang, Q.-R. (2018). Expression and clinical significance of the NEK7-NLRP3 inflammasome signaling pathway in patients with systemic lupus erythematosus. Journal of Inflammation, 15(1), 16. https://doi.org/10.1186/s12950-018-0192-9
Mähönen, K., Hau, A., Bondet, V., Duffy, D., Eklund, K. K., Panelius, J., & Ranki, A. (2022). Activation of NLRP3 Inflammasome in the Skin of Patients with Systemic and Cutaneous Lupus Erythematosus. Acta Dermato-Venereologica, 102, adv00708. https://doi.org/10.2340/actadv.v102.2293
Mittal, R., Saavedra, D., Mittal, M., Lemos, J. R. N., & Hirani, K. (2025). Inflammasome activation and accelerated immune aging in autoimmune disorders. Frontiers in Aging, 6. https://doi.org/10.3389/fragi.2025.1688060
Neamțu, M., Bild, V., Vasincu, A., Arcan, O. D., Bulea, D., Ababei, D.-C., Rusu, R.-N., Macadan, I., Sciucă, A. M., & Neamțu, A. (2024). Inflammasome Molecular Insights in Autoimmune Diseases. Current Issues in Molecular Biology, 46(4), 3502–3532. https://doi.org/10.3390/cimb46040220
Rodríguez-Carrio, J., Burska, A., Conaghan, P. G., Dik, W. A., Biesen, R., Eloranta, M.-L., Cavalli, G., Visser, M., Boumpas, D. T., Bertsias, G., Wahren-Herlenius, M., Rehwinkel, J., Frémond, M.-L., Crow, M. K., Ronnblom, L., Vital, E., & Versnel, M. (2023). Association between type I interferon pathway activation and clinical outcomes in rheumatic and musculoskeletal diseases: a systematic literature review informing EULAR points to consider. RMD Open, 9(1), e002864. https://doi.org/10.1136/rmdopen-2022-002864
Tian, J., Zhou, H., Li, W., Yao, X., & Lu, Q. (2025). New Mechanisms and Therapeutic Targets in Systemic Lupus Erythematosus. MedComm, 6(6), e70246. https://doi.org/10.1002/mco2.70246
Wang, X., Fu, S., Yu, J., Ma, F., Zhang, L., Wang, J., Wang, L., Tan, Y., Yi, H., Wu, H., & Xu, Z. (2023). Renal interferon-inducible protein 16 expression is associated with disease activity and prognosis in lupus nephritis. Arthritis Research & Therapy, 25(1), 112. https://doi.org/10.1186/s13075-023-03094-8
Wang, X., Wen, B., Duan, X., Zhang, Y., Hu, Y., Li, H., Shang, H., & Jing, Y. (2025). Recent Advances of Type I Interferon on the Regulation of Immune Cells and the Treatment of Systemic Lupus Erythematosus. Journal of Inflammation Research, 18, 4533–4549. https://doi.org/10.2147/JIR.S516195
Xu, Y., Biby, S., Kaur, B., & Zhang, S. (2023). A patent review of NLRP3 inhibitors to treat autoimmune diseases. Expert Opinion on Therapeutic Patents, 33(6), 455–470. https://doi.org/10.1080/13543776.2023.2239502
Zhang, L., Wei, X., Wang, Z., Liu, P., Hou, Y., Xu, Y., Su, H., Koci, M. D., Yin, H., & Zhang, C. (2023). NF-κB activation enhances STING signaling by altering microtubule-mediated STING trafficking. Cell Reports, 42(3), 112185. https://doi.org/10.1016/j.celrep.2023.112185
Zhang, Y., Yang, W., Li, W., & Zhao, Y. (2021). NLRP3 Inflammasome: Checkpoint Connecting Innate and Adaptive Immunity in Autoimmune Diseases. Frontiers in Immunology, 12. https://doi.org/10.3389/fimmu.2021.732933
Zhong, S., Zhou, Q., Yang, J., Zhang, Z., Zhang, X., Liu, J., Chang, X., & Wang, H. (2024). Relationship between the cGAS−STING and NF-κB pathways-role in neurotoxicity. Biomedicine & Pharmacotherapy, 175, 116698. https://doi.org/10.1016/j.biopha.2024.116698
