Infection-sensing Protein Overactive in Patients’ Immune Cells, Study Says
A molecular sensor of infections called the NLRP3 inflammasome is overactive in immune cells of people with Rett syndrome, a new study reveals.
The study, “The constitutive activation of TLR4-IRAK1- NFκB axis is involved in the early NLRP3 inflammasome response in peripheral blood mononuclear cells of Rett syndrome patients,” was published in Free Radical Biology and Medicine.
A neurodevelopmental disorder, Rett syndrome causes abnormalities in a number of bodily systems and people with Rett generally have more inflammation in their bodies. The reasons for this, however, remain poorly understood.
An international team led by scientists in Italy collected blood samples from 20 Rett patients (mean age 15.2), along with blood from 11 healthy people of similar age for comparison. Next, the researchers analyzed peripheral blood mononuclear cells (PBMCs), a broad group of immune cells that includes B-cells, T-cells, and monocytes. Specifically, the team assessed the activity of the NLRP3 inflammasome.
The protein NLRP3 (nucleotide-binding domain and leucine-rich repeat-containing protein 3) acts as a sensor for infectious bacteria and other dangers. When it detects danger, it sounds the alarm by binding to other proteins to form a structure called an inflammasome.
The inflammasome triggers the cell to undergo a form of inflammatory cell death called pyroptosis, triggered by inflammation and usually caused by microbial infection. This leads to pro-inflammatory signaling molecules, particularly interleukin-1 beta (IL-1B) and IL-18, being released to alert the immune system of the threat.
Through a battery of biochemical experiments, the researchers demonstrated that the NLRP3 inflammasome was overly active in PBMCs from Rett patients. Consistently, levels of IL-1B and IL-18 were elevated in their blood.
Nearly all Rett syndrome cases — including all 20 included in this study — are caused by mutations in the gene MECP2. The researchers showed in subsequent experiments that genetically manipulating cells to reduce MECP2 activity could increase the activity of inflammasome-associated proteins.
Overall, the results suggest abnormal activity of the NLRP3 inflammasome in Rett syndrome, which points to “a role of this machinery in the subclinical inflammatory status, present in the disease,” the researchers wrote.
Specific MECP2 mutations are generally associated with more or less severe disease. The researchers found that patients with more severe mutations tended to have higher levels of IL-1B, while levels of IL-18 were not associated with mutation.
Other analyses showed that IL-18 levels tended to be higher early in the disease course, compared to those with more advanced disease. This might indicate that IL-18 plays a key role in chronic inflammation and altered energy production in cells over Rett’s disease course, researchers speculated.