Northwestern Medicine scientists have identified a previously unknown key regulator of inflammasomes, a first-line immune response. The stress-activated regulator, a protein kinase known as Jnk2, promotes a physiological process called mitophagy that helps maintain cellular homeostasis.
Homeostasis is a healthy equilibrium in the body achieved through many self-regulated processes, including mitophagy, which removes damaged or excessive mitochondria from cells. When these energy-producing organelles aren’t disposed of properly, groups of proteins called inflammasomes are hyper-activated, which can lead to fatal tissue and organ damage.
The new study, published in Nature Immunology, shows that Jnk2 stimulates mitophagy, which prevents hyperactivation of the NLRP3 inflammasome multiprotein complex and maintains immune homeostasis.
“Since discovered in 2002, inflammasomes have been extensively studied. However, the regulatory mechanism that fine-tunes the activity of inflammasome has been incompletely understood,” said senior author Jing Liu, PhD, assistant professor in Medicine-Pulmonary. “Our finding provides an important breakthrough in the field of immunity.”
The finding suggests that promoting mitophagy by way of Jnk2 may protect organs from damage induced by sepsis, a complication of infection that occurs when immune response chemicals fighting harmful bacteria and toxins spread through the bloodstream and cause inflammation throughout the body.
“Our work also implies that targeting Jnk2-regulated mitophagy for tissue tolerance to damage may have broad applications to many pathological conditions that are associated with mitochondrial dysfunction, such as sepsis,” Liu said.
In the study, loss of Jnk2 in mouse models resulted in tissue damage under hypoxic stress, inflammasome hyperactivation and increased mortality from sepsis. They also discovered that Jnk2 targets a small mitochondrial form of a tumor suppressor called ARF, which was previously reported to induce mitophagy when over-expressed.
“Jnk2 functions as a guardian for organ integrity and thereby determines life or death under environmental stress,” the study’s authors write in the paper.
Future research will continue to examine the applications of this important protein.
“One potential translational aspect of our work is to determine whether JNK2 serves as a marker of severe sepsis and prognosis in the intensive care unit,” Liu said.
This study was supported by National Institutes of Health National Heart, Lung, and Blood Institute grant HL114763 and American Asthma Foundation grant 13-0114.