Kallikrein-kinin system and regulation of lupus autoimmunity: pathways from periphery to brain

Temple Univ Of The Commonwealth, Philadelphia PA

Investigators

Abstract

Project summary: Neuropsychiatric Lupus (NPSLE) is a common but under-researched aspect of systemic lupus erythematosus (SLE). Symptoms include anxiety, depression, and cognitive impairment. NPSLE severity varies, indicating a complex pathogenesis. Excessive Type I interferon (IFN) production and response is a hallmark of SLE. High IFNα levels correlate with depression and anxiety in lupus patients and mice. Targeting theType I IFN response is a therapeutic goal. The FDA has approved anifrolumab, an anti-IFN receptor antibody, for moderate to severe lupus; however, its efficacy in NPSLE remains untested. IFNAR blocking in pre-clinical models has shown varied outcomes, suggesting complex IFN regulation in different lupus models and highlighting the need for alternative IFN suppression pathways. Our research discovered that the kallikrein-kinin system (KKS) can suppress Type I IFN response, introducing a new pathway for IFN suppression. KKS regulates many physiological processes, including inflammation and brain functions. KKS components, including kallikreins and bradykinins, along with ACE inhibitors (ACEi), suppress IFN responses in lupus models. Administering the ACEi captopril in lupus mice reduced IFN gene expression, neuroinflammation, and depressive behavior. Exogenous kallikrein-1 (klk1) also improved depressive behavior and reduced IFNα levels in lupus mice. NPSLE symptoms appear early in lupus, indicating a role of peripheral autoimmunity. Brain-reactive antibodies, cytokines, and inflammation contribute to NPSLE pathogenesis. Extracellular vesicles (EVs) from SLE patients carry inflammatory cargo and may influence NPSLE. High levels of cell-free DNA (cf-DNA) is found in SLE patients and the importance of cf-DNA as a biomarker and immune mediator is researched extensively. Reducing peripheral IFNα could reduce CNS inflammation and improve symptoms. We hypothesize that excessive peripheral IFNα, production and response, causes NPSLE. Reducing IFN responses with ACEi and klks will decrease CNS inflammation and behavioral symptoms. In aim 1, we will dissect the cellular and molecular mechanisms by which the KKS and ACEi modulate IFN pathways. Using DC and microglia as cell models, we will analyze these mechanisms in the periphery and brain, respectively, in established NPSLE models (MRL/lpr and NZBW/F1), and in the new microglia specific IFNAR-knockout B6/lpr model. We will correlate these molecular mechanisms with behavioral outcomes. In aim 2, we will analyze the pathways by which peripheral immune responses affect neuroinflammation and behavior in the models in Aim 1. We will focus on the effects of circulating peripheral components (EVs and cf-DNA) from mouse and human cells on brain cells (primary mouse cells or human cell-lines). We will also analyze parallels in IFN-KKS related gene/protein profiles in EVs from lupus patients’ samples (SLE and NPSLE). These studies aim to (1) elucidate the therapeutic potential of KKS molecules in SLE and NPSLE, (2) understand the mechanisms of ACE inhibitors, (3) identify and validate novel peripheral biomarkers for NPSLE prognosis, and (4) provide insights into peripheral-brain interactions in chronic inflammation.