A recent study has identified NLRC5 as a crucial innate immune sensor that is involved in PANoptotic cell death. This discovery makes NLRC5 a significant target for therapeutic interventions. The innate immune system is responsible for protecting the body from potential threats that can lead to illness or infection. It relies on innate immune sensors to detect and transmit signals about these threats. Cell death is a key strategy used by the innate immune system to respond to these threats. The research from St. Jude Children’s Research Hospital has revealed that NLRC5 plays a previously unknown role as an innate immune sensor, triggering cell death.Results published in the journal Cell demonstrate the role of NLRC5 in driving PANoptosis, a significant type of inflammatory cell death. This discovery has important implications for the development of treatments targeting NLRC5 for the management of infections, inflammatory conditions, and the aging process.
In response to different threats, innate immune sensors can form complexes such as inflammasomes or PANoptosomes. The inflammasome acts as a rapid emergency broadcast system, while the PANoptosome functions as an emergency response unit that generally integrates more signals and components to address the threat. This innate immune response is crucial for maintaining the body’s overall health and well-being.The way immune sensors operate, and what makes them take action, has been a puzzle that researchers have been trying to solve for many years. Nucleotide-binding oligomerization domain-like receptors (NLRs) are a family of important molecules involved in signaling inflammation. They are believed to serve as innate immune sensors that detect threats. However, the specific functions of several NLRs in sensing are still not fully understood. Scientists at St. Jude conducted a large screening process to test a specific NLR, NLRC5, in order to identify what threats activate it. Through their research, they found that depletion of nicotinamide adenine dinucleotide (NAD+) was a trigger for NLRC5.NAD, an important molecule for producing energy, activates NLRC5-mediated cell death through PANoptosis.
“A major question in the fields of immunology and innate immunity is understanding what the different members of the NLR family are sensing and what their functions are,” explained Thirumala-Devi Kanneganti, PhD, vice chair of the St. Jude Department of Immunology and corresponding author of the study. “NLRC5 was a mysterious molecule, but now we have the answer – it serves as an innate immune sensor and regulates cell death, driving inflammatory cell death, PANoptosis, by forming a complex.”
Discovering the NLRC5 trigger
ResearchersResearchers in the Kanneganti lab conducted an extensive study to uncover the triggers for NLRC5. They examined a range of pathogens including bacteria and viruses, as well as pathogen associated molecular patterns (PAMPs) and damage associated molecular patterns (DAMPs) that can be released by infections or injuries, along with other danger signals like cytokines (immune signaling molecules).
The team also investigated heme, the part of hemoglobin that carries oxygen. Infections or disease can lead to the rupture of red blood cells in a process known as hemolysis, which releasesThe breakdown of hemoglobin in the bloodstream releases free heme, which can cause inflammation and organ damage. Researchers experimented with different combinations of pathogens, PAMPs, and DAMPs to determine if NLRC5 was necessary for a response. “Among all the combinations we tested, we found that the combination of heme plus PAMPs or cytokines specifically triggers NLRC5-dependent inflammatory cell death, PANoptosis,” said co-first author Balamurugan Sundaram, PhD, from the St. Jude Department of Immunology. “Our findings demonstrate for the first time that NLRC5 plays a crucial role in reacting to hemolysis, a condition that can happen during infections, inflammatory illnesses, and cancer.”
Power shortage activates NLRC5
After identifying the heme-containing PAMP, DAMP, and cytokine combinations that cause NLRC5-dependent inflammatory cell death, the scientists delved into how NLRC5 is controlled. They discovered that NAD levels influence NLRC5 protein expression. When NAD is low, it signals a potential threat that the immune system needs to recognize. The researchers also learned that NLRC5 senses the depletion of NAD, triggering PANoptosis.
“By supplementing with rnrnCo-first author Nagakannan Pandian, PhD, from the St. Jude Department of Immunology, stated that by reducing the NLRC5 protein expression through the NAD precursor, nicotinamide, they were able to induce PANoptosis. He also mentioned that nicotinamide has been widely studied as a nutrient supplement and their findings suggest its potential in treating inflammatory diseases.
Furthermore, the researchers found that NLRC5 is part of an NLR network with NLRP12, and together with other cell death molecules, they form an NLRC5-PANoptosome complex that triggers inflammatory cell death. This discovery builds on previous research by the Kanneganti lab on the role of NLRP12 in PANoptosis.
An appealing focus for therapeutic advancement
NLRs are linked to diseases involving infection, inflammation, cancer, and aging. This makes them an intriguing focus for the development of new treatments. Research conducted by the Kanneganti lab demonstrates that removing Nlrc5 can offer protection against inflammatory cell death through PANoptosis and prevent disease progression in hemolytic and inflammatory disease models, making NLRC5 a promising candidate for therapeutic development.
“The foundational understanding we have gained regarding the functioning of innate immune sensing can be applied to a wide range of therapeutic developments,” explained the researchers.
Kanneganti noted that this new approach could potentially be beneficial for a wide range of diseases and conditions, including aging, infectious disease, and inflammatory disorders, for which there are currently no targeted therapies.
The other authors of the study include Emily Alonzo from the Department of Research and Development at Cell Signaling Technology, as well as Hee Jin Kim, Hadia Abdelaal, Omkar Indari, Roman Sarkar, Rebecca Tweedell, Jonathan Klein, Shondra Pruett-Miller, and Peter Vogel from St. Jude. Raghvendra Mall, formerly of St. Jude and now of the Technology Innovation Institute in Abu Dhabi, also contributed to the study.
The research was funded by grants from the National Institutes of Health (AI101935, AI124346, AI160179, AR056296, and CA253095) as well as ALSAC, which is the fundraising and awareness organization of St. Jude.
