Relieving ER stress in lupus neutrophils

Neutrophils, a type of immune cell, fight infections by squirting out DNA molecules known as NETs. In patients with lupus, neutrophils may be under stress, which could spur them to release their DNA even in the absence of an infection. Our study will test whether a networks of tubes in the cells known as the endoplasmic reticulum plays a key role in NET release. We suspect that the endoplasmic reticulum detects when neutrophils are under stress and then stimulates the cells to produce NETs. The research will test whether a stress-sensing protein in the endoplasmic reticulum spurs neutrophils from patients with lupus to release NETs. We will also ask whether molecules that block this protein reduce lupus symptoms in mice.

What this study means to people with lupus

“Some immune cells spray out their own DNA to trap bacteria, but in lupus this DNA can provoke the immune system to attack patients’ own cells. We aim to determine how a type of cell stress may lead to release of this DNA. Our research could point to new drug targets for treating lupus.”

Neutrophils have been implicated as perpetuators of the lupus phenotype, with a peripheral-blood “neutrophil signature” predicting lupus flares in at least a subset of patients. Recent work has revealed that the formation of mitochondrial reactive oxygen species (ROS) by lupus neutrophils is a driver of mitochondrial DNA oxidation and a prerequisite for the release of interferogenic neutrophil extracellular traps (NETs). However, the upstream regulators of mitochondrial ROS in lupus neutrophils remain undefined. The endoplasmic reticulum (ER) is an endomembrane compartment that is highly sensitive to inflammatory and oxidative perturbation. Our hypothesis is that the ER acts as an indispensable relay station between stressors (like autoantibodies) and NET release (NETosis) in lupus neutrophils. INNOVATION: Our preliminary data reveal that the ER stress sensor inositol-requiring enzyme 1a (IRE1a) regulates mitochondrial ROS formation in lupus neutrophils, and that inhibition of IRE1a blocks lupus autoantibody-mediated NETosis. SPECIFIC AIMS: Aim 1 will be to define the IRE1a circuitry that regulates mitochondrial ROS and NETosis in response to lupus autoantibodies. Aim 2 will be to measure neutrophil IRE1a activity in lupus patients, and the extent to which it predicts plasma oxidized mitochondrial DNA and disease activity. Aim 3 will be to determine the extent to which inhibition of the IRE1a pathway mitigates manifestations of murine lupus and antiphospholipid syndrome (APS). IMPACT: More precisely understanding the cellular signals that perpetuate inflammation and autoimmunity in lupus is of paramount importance as we attempt to maximize the efficacy—and minimize the toxicity—of the therapies we prescribe. This work will contribute to a better understanding of disease heterogeneity (and potentially delineate novel therapeutic targets) by characterizing ER stress responses in lupus neutrophils.