Stress Triggers Proinflammatory Axis in Neuropsychiatric Lupus

Scientists at the Hokkaido University in Japan have identified a stress-induced molecular pathway that affects neuropsychiatric systemic lupus erythromatosus (NPSLE). The mechanistic insight could potentially reveal new molecular targets for treating the disease that currently has no cure.

The findings were published in an article titled “Pathogenic neuropsychiatric effect of stress-induced microglial interleukin-12/23 axis in systemic lupus erythematosus” in the journal Annals of the Rheumatic Diseases, on July 11, 2022.

“In revealing the effect of the stress-induced effects on the expression of IL-12 and IL-23 in dNPSLE, we have identified them as not only a diagnostic marker but also a novel therapeutic target for this disease,” said Masaaki Murakami, PhD, a professor at the Institute for Genetic Medicine at Hokkaido University and the senior author of the study.

NPSLE is a severe form of the autoimmune disorder, systemic lupus erythematosus (SLE) where the immune system attacks the body’s own cells and tissues. Unlike SLE that can flare up in all organs of the body, NPSLE specifically affects the brain and spinal cord resulting in neurological and psychiatric manifestations. Current treatments involve preventing flare ups and reducing their severity and duration.

The authors focused on a specific type of NPSLE with diffuse neuropsychological manifestations (dNPSLE), the pathology of which is poorly understood.

Chronic stress is involved in the development of different autoimmune diseases. Earlier studies have shown, stress changes the activation status of neurons and glial cells in the brain and spinal cord, leading to neuroinflammation. Therefore, the investigators focused on the molecular mechanisms underlying the effects of stress on dNPSLE. A variety of factors affect dNPSLE, including blockages in blood vessels, malfunctions in the blood–brain barrier, cytokines, autoantibodies and direct damage of neurons.

Upon subjecting lupus-prone model mice to sleep deprivation to simulate stress, the researchers analyzed behavioral phenotypes, histopathology, and the expression of genes and proteins to assess neuroimmunological changes. In addition to studies on mice, the investigators also measured cytokines in the cerebrospinal fluid and volumes of various brain regions in patients with dNPSLE and controls.

Sleep deprivation in lupus-prone mice, the authors observed, resulted in abnormal activation of the medial prefrontal cortex (mPFC) of the brain. Transcriptomic analysis of the mPFC in these mice revealed that the expressions of over 500 genes were significantly altered upon sleep deprivation stress. In particular, the authors found sleep deprivation increased the expression of microglial activation-related genes, including IL-12b. The authors showed, the upregulation of IL-12 and IL-23 caused microglial activation in mPFC in model mice. They confirmed microglial activation led to the upregulation of proteins in the IL-12/23p40 pathway and in the abnormal increase of dendritic spines in the mPFC. Blocking IL-12 and IL-23 pathways in these sleep-deprived mice models inhibited the stress-induced neuropsychiatric symptoms.

Patients with dNPSLE also had increased levels of IL12 and IL23 in the cerebrospinal fluid compared to healthy individuals, the authors showed. These cytokines could therefore act as diagnostic markers. In addition, the researchers found reduced volume of the mPFC in patients, indicating atrophy.