A protein known as p62 is central to regulating inflammation in the body, to avoid excessive damage while eliminating infectious agents and toxic chemicals, said NIEHS-funded researchers at the University of California, San Diego (UCSD), in a study published Feb. 25 in the journal Cell. Inflammation is important for clearing foreign irritants, such as environmental chemicals, from the body, but excessive inflammation can harm cells and lead to irreversible organ damage and even fatality.
In the body, the NF-kappaB (NF-kB) protein complex has well-known proinflammatory functions, although it also keeps inflammation in check to prevent problems caused by excessive inflammatory responses. Until now, the underlying mechanisms were not clearly understood. This study in mice shows that NF-kB exerts its inflammation regulatory role by increasing the production of p62. In turn, p62 helps eliminate damaged mitochondria in macrophages, and thus, prevents certain inflammatory processes.
Led by Michael Karin, Ph.D., distinguished professor of pharmacology and pathology at UCSD School of Medicine, the study was conducted as part of the UCSD Superfund Research Program (SRP) Center. “The objective of the UCSD SRP Center is to work toward defining the molecular and genetic basis of the biological effects of toxicant exposure,” said Michelle Heacock, Ph.D., NIEHS health scientist administrator.
“This research has uncovered a key process in the body that controls inflammation that results from environmental chemicals and other foreign invaders, and helps us understand how toxicants affect our health,” she said.
Studying the inflammation process
The immune system uses a complex set of signals and processes to respond to unwanted substances and remove them from the body. Upon detection of cellular debris or foreign substances, macrophages are activated, which then engulf and digest the unwanted substances. These cells use multiprotein complexes called inflammasomes to produce proteins known as cytokines.
After tissue injury, the NLRP3-inflammasome mediates the maturation and release of proinflammatory cytokines, such as interleukin 1beta (IL-1B). Release of IL-1B initiates a cascade of responses that ultimately help the body clear foreign particles, promote tissue repair, and restore homeostasis. However, continuous production of IL-1B can cause collateral damage as a result of excessive inflammation, which leads to organ failure and even death.
NF-kB is involved in both inducing NLRP3-inflammasome, and keeping it in check. Karin’s team found that foreign particle damage to the macrophage’s mitochondria, where the cell produces energy, causes the mitochondria to release signals that activate NLRP3-inflammasome in macrophages, leading to more IL-1B production. Mechanistically, NF-kB regulates this IL-1B production by increasing the production of p62, which coats damaged mitochondria and eliminates them. Once the damaged mitochondria are removed, the inflammasome pathway to produce IL-1B is turned off.
Implications for disease prevention
“In addition to explaining how our bodies can turn off inflammation when it’s no longer needed, these findings could have important implications for many age-related diseases,” Karin said in a press release.
Poor regulation of NLRP3-inflammasomes is associated with a number of diseases, including gouty arthritis, Alzheimer’s disease, obesity, type 2 diabetes, and colorectal cancer. Because control of NLRP3-inflammasome activity is critical for preventing disease development, understanding this control process may help us to understand, and potentially help prevent, these inflammatory and metabolic diseases.
Citation: Zhong Z, Umemura A, Sanchez-Lopez E, Liang S, Shalapour S, Wong J, He F, Boassa D, Perkins G, Raza Ali S, McGeough MG, Ellisman MH, Seki E, Gustafsson AB, Hoffman HM, Diaz-Meco MT, Moscat J, Karin M. 2016. NF-KB restricts inflammasome activation via elimination of damaged mitochondria. Cell 164(5):896-910.
(Sara Mishamandani is a research and communication specialist for MDB Inc., a contractor for the NIEHS Division of Extramural Research and Training.)