April 28, 2021
In a new study led by Dr. Jason S. Knight and funded by the Lupus Research Alliance, researchers found a way to block inflammation by targeting a key protein, IRE1α, found in immune cells that are active in lupus, known as neutrophils. Dr. Knight’s team found that this protein could control some of the neutrophil actions that cause inflammation in lupus patients. Being able to better control cells that cause inflammation should help decrease tissue damage and lessen organ damage in lupus patients.
Researchers took neutrophils from healthy people without lupus and fed the cells a mixture of proteins that would usually trigger inflammation in lupus patients (also called immune complexes). In response to this mixture, the neutrophils activated a protein called IRE1a. Researchers then checked blood cells from lupus patients and also saw high IRE1a activity. Additionally, researchers found that increased disease activity in lupus patients was linked to increased IRE1a activity.
After determining that IRE1a was linked to lupus disease activity, researchers wanted to know if IRE1a played a role in increasing the inflammation that causes damage in lupus. One trigger of inflammation are chemicals known as reactive oxygen species (ROS). Since ROS are an important chemical switch for promoting inflammation, researchers wanted to see if ROS activity increased in the same way that IRE1 increased.
Researchers set up the experiment with the immune complexes again but instead of measuring IRE1a, they measured ROS (higher ROS = increased inflammation). Like IRE1a, cells also increased ROS after being exposed to the immune complex. Next, researchers added a chemical to the cells that blocks IRE1a activity before giving the immune complexes and found that the IRE1a blocker was also able to block ROS. To see if this pattern also happened in a living model over a longer period of time, researchers triggered inflammation in living mice and gave them the IRE1a blocker at the same time. After six weeks, the scientists looked at the cells from the mice and found that the mice that were given the IRE1a blocker had less inflammation. Excitingly, this also confirmed the results they obtained from the previous experiments with human cells.
Now that the researchers determined that IRE1a may be linked to inflammation caused by ROS, they investigated whether IRE1a was connected to another cellular response in lupus called NETosis. When exposed to a substance that may be dangerous, neutrophils release sticky DNA and protein webs called NETs; the release of NETs from neutrophils is known as NETosis. Similar to ROS, NETosis also triggers inflammation and leads to tissue damage in lupus. Researchers found that triggering inflammation in mice and giving them an IRE1a blocker lessened NETosis. The neutrophils stayed healthy and the number of neutrophils in the mice did not change with the IRE1a blocker, showing that the blocker did not indiscriminately kill all neutrophils, which is important because neutrophils are also required for many of the body’s normal functions.
Lastly, the researchers also treated a well-established mouse model of lupus with IRE1a blockers and again found lower levels of both ROS and NETosis. The “lupus mice” that received the IRE1a blockers had less enlarged spleens and weighed less, which may indicate less inflammation. These mice also had fewer cells called plasma cells, which are important producers of bad antibodies in lupus.
This study shows that IRE1a can affect NETosis and ROS in neutrophils. Researchers suggest that understanding how to better control NETosis and ROS could help treat inflammation in lupus and other diseases.
“This study sheds light on a new path of events in the cell contributing to the inflammation occurring in lupus, comment Dr. Knight. “Hopefully, future research will lead to a treatment for humans that targets this inflammation to lessen or eliminate lupus’ damaging effects.”