Kallikrein-kinin system: novel regulators in systemic and neurolupus
Uma Sriram1, Viviana Zuluaga-Ramirez1, Alecia Seliga1, Steven Franklin Merkel1, Malika Winfield1, Nicole C. Fernandes1, Michael Hweemoon Lee2, Sachin Gajghate1, Stefania Gallucci2 and Yuri Persidsky1
1Department of Pathology and Laboratory Medicine, 2Department of Microbiology and Immunology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by multi-organ damage. Interferon-α (IFN-α) is a central mediator in disease pathogenesis. Neuropsychiatric lupus (NPSLE) is one of the most common manifestations of human SLE often causing depression. Administration of IFN-α in patients with chronic viral infections or cancers causes depressive symptoms. The Kallikrein-Kinin System (KKS), comprised of kallikreins (klks), bradykinins (BKs) angiotensin converting enzyme (ACE) and other molecules, regulates many physiological processes, including inflammation and regulates brain functions. We have shown that myeloid dendritic cells (DCs) from Sle 1,2,3 (Sle) lupus-prone mouse model show a Type I IFN signature that predates disease onset. We used DCs from Sle and age-matched control C57BL/6 (B6) mice and treated with CpG (TLR9 ligand), R848 (TLR7 ligand) or recombinant IFN-α to induce Interferon Stimulated Genes (ISGs) and treated with molecules of the KKS. We used the MRL/lpr lupus-prone mouse model to check effects in NPSLE.
Sle DCs exhibited decreased expression of klk genes compared to B6 DCs. TLR7/9 or IFN-α induced ISG expression was markedly diminished by BKs, klk1 (tissue klk) or captopril (ACE inhibitor) in B6 mice. BKs also suppressed ISGs induced by CpG in vivo in B6 and Sle mice. Exposing MRL/lpr mice to IFN-α increased depressive-like behavior, decreased klk expression, and enhanced ACE expression in the brain. ACE activity decreases BK levels; administering captopril decreased ISG expression in brain and kidney. The KKS-IFN cross-regulatory pathway may provide a rationale for therapeutic use of KKS molecules for treatment of systemic and neurolupus.