The innate immune system is essential for protecting the body from threats that could cause disease or infection. This system relies on innate immune sensors to detect and transmit signals about these threats. Cell death is one of the key strategies used by the innate immune system to respond to these threats. Recent research from St. Jude Children’s Research Hospital has identified NLRC5 as a previously unknown innate immune sensor that triggers PANoptosis, a type of inflammatory cell death. This discovery has implications for the development of therapeutics targeting NLRC5 for the treatment of infections, inflammatory diseases, and aging.
Innate immune sensors can assemble complexes such as inflammasomes or PANoptosomes in response to different threats. The inflammasome acts as an emergency broadcast system, while the PANoptosome is an emergency response unit that integrates more signals and components. Researchers have been working to understand how innate immune sensors are triggered to act for decades. Nucleotide-binding oligomerization domain-like receptors (NLRs) are a family of molecules involved in inflammatory signaling and are thought to function as innate immune sensors. The specific roles of some NLRs in sensing are still unclear. St. Jude scientists conducted a large screen to test NLRC5, revealing that depletion of nicotinamide adenine dinucleotide (NAD) triggers NLRC5-mediated cell death through PANoptosis.
The mysterious role of NLRC5 in innate immunity was investigated by researchers in the Kanneganti lab. By conducting a thorough screen, they discovered that NLRC5 acts as an innate immune sensor and cell death regulator. NLRC5 drives PANoptosis by forming a complex in response to specific threats. The team looked at pathogens, PAMPs, DAMPs, cytokines, and heme, the component of hemoglobin that causes inflammation and organ damage when released into the bloodstream. Their research demonstrated that NLRC5 plays a central role in responding to hemolysis, which can occur during infections, inflammatory diseases, and cancers.
Further research by the Kanneganti lab explored how NLRC5 is regulated, uncovering that NAD levels control NLRC5 protein expression. Depletion of NAD triggers NLRC5-mediated cell death, suggesting a potential therapeutic target. By supplementing with nicotinamide, a NAD precursor, NLRC5 protein expression and PANoptosis can be reduced. This finding indicates that nicotinamide supplementation could be beneficial in treating inflammatory diseases. The researchers also identified an NLR network involving NLRC5 and NLRP12, forming an NLRC5-PANoptosome complex that triggers inflammatory cell death, building on previous research showing NLRP12’s role in PANoptosis.
NLRs are implicated in diseases related to infection, inflammation, cancers, and aging, making them attractive targets for therapeutic development. Deleting Nlrc5 can protect against inflammatory cell death and disease pathology in models of hemolytic and inflammatory diseases, highlighting NLRC5 as a potential therapeutic target. The research conducted at St. Jude provides fundamental knowledge into how innate immune sensing works, which could be applied to various diseases and conditions. This knowledge has the potential to lead to the development of targeted therapies for aging, infectious diseases, and inflammatory disorders where no specific treatments are currently available.
