The innate immune system is responsible for protecting the body from threats that may cause disease or infection. The system relies on innate immune sensors to detect and transmit signals about these threats. One of the main hereditary immune strategies to respond to threats is cell death. New research from St. Judah Children's Research Hospital has revealed that the NLRC5 plays a previously unknown role as the role of a congenital immune sensor, causing cell death. The results, published in Cell, show how NLRC5 promotes PANoptosis, a prominent form of inflammatory cell death. 

This understanding has implications for the development of drugs that target NLRC5 to treat infections, inflammatory diseases, and aging. Depending on the threat, innate immune sensors can form complexes such as inflammasomes or PANoptosomes. The Inflammasome can be thought of as a quick-launch emergency dispatch system, while the PANoptosome is more of an emergency response device that typically integrates multiple signals and components to respond to threats. How innate immune sensors work—what makes them tick—has been a mystery that has puzzled scientists for decades.

Nucleotide-binding oligomerization domain-like receptors (NLRs) are an important family of molecules involved in inflammatory signaling. They are generally thought to act as innate immune system sensors that detect threats. However, the specific roles of several NLRs in sensing are not yet understood. Scientists at St. Jude conducted a large screen, testing a specific NLR, NLRC5, to see what threats activate it. Through their efforts, they discovered that depletion of nicotinamide adenine dinucleotide (NAD), a molecule essential for energy production, leads to NLRC5-mediated cell death through PANoptosis.

"One of the big questions in immunology and innate immunity is what the different members of the NLR family sense and what their functions are," said corresponding author Thirumala-Devi Kanneganti, Ph.D. from the St. Petersburg department. Jew. "NLRC5 is an enigmatic molecule, but we now have an answer—it functions as an innate immune sensor and cell death regulator that, when forming a complex, promotes inflammatory cell death known as holoapoptosis."

Identifying the NLRC5 trigger

Cannegant laboratory researchers are strictly tested to reach the lower part of the NLRC5 causing threat. These include pathogens such as bacteria and virus, as well as pathogen -related molecular patterns (PAMPs) and damage -related molecular patterns (wet). The researchers also looked at heme, the component of hemoglobin responsible for carrying oxygen. Infection or disease can cause red blood cells to burst during hemolysis. This releases hemoglobin into the blood. When hemoglobin breaks down into its components, it releases free heme, which is known to cause severe inflammation and organ damage. The researchers tested many different combinations of pathogens, PAMPs, and DAMPs to determine whether NLRC5 was required for the response.

"Of all the combinations we tested, we found that the combination of heme and PAMPs or cytokines specifically induced NLRC5-dependent inflammatory cell death, known as PANoptosis," said co-author Balamurugan Sundaram, Ph.D., Institute of Immunology at St. Jew. "Our results show for the first time that NLRC5 is critical for hemolytic reactions that can occur during infections, inflammatory diseases and cancer."

Energy depletion triggers NLRC5 function

After finding that a combination of heme-containing PAMPs, DAMPs, and cytokines induces NLRC5-dependent inflammatory cell death, the researchers went on to investigate how NLRC5 is regulated. They found that NAD levels promote NLRC5 protein expression. If NAD is exhausted, this sounds like a warning that the immune system should identify a threat. Researchers have found that NLRC5 -Sensing of NAD emptying is triggered. "In addition to Nad-Forer, nicotinamide, we reduced NLRC5 protein expression and panoptosis," said Nagakannan Pandian, PhD, St. St. Judas Immunology Department.  "Therapeutic, nicotinamide is widely tested as a dietary supplement, and our findings show that it could be useful for the treatment of inflammatory diseases."

The researchers also found that the NLRC5 is located on the NLR network with NLRP12, which, along with other cell death molecules and forms the NLRC5 Panoptosome Complex, which causes the death of inflammatory cells. The finding builds on previous research from the Kanneganti lab showing the role of NLRP12 in PANoptosis.

A  promising target for therapeutic development

NLR has been linked to infections, inflammation, cancer and aging-related diseases. This makes them interesting targets for the development of new therapies. Work from the Kanneganti lab shows that deletion of Nlrc5 confers protection against inflammatory cell death via PANoptosis and prevents disease pathology in hemolytic and inflammatory disease models, making NLRC5 an exciting therapeutic prospect.

"The basic knowledge we're gaining about how innate immunity works can translate to many diseases and conditions," Caneganti said. "Aging, infectious diseases, inflammatory disorders -- things that don't have targeted treatments, this could be an option."