Researchers have puzzled over how innate immune sensors function for decades. However, this is about to change thanks to a groundbreaking discovery by scientists at St. Jude Children’s Research Hospital. They have uncovered a previously unknown role of NLRC5 as an innate immune sensor.

Featured in the scientific journal Cell, the study investigated what triggers NLRC5, a member of the nucleotide-binding oligomerization domain-like receptors (NLRs) family in the human body.

“NLRC5 was an enigmatic molecule, but now we have the answer – it is acting as an innate immune sensor and cell death regulator, driving inflammatory cell death, PANoptosis, by forming a complex,” said Dr. Thirumala-Devi Kanneganti, St. Jude Department of Immunology vice chair and corresponding author of the study.

After screening potential threats that could activate NLRC5, researchers in the Kanneganti lab found that heme, combined with cytokines or pathogen-associated molecular patterns (PAMPs), primarily triggers NLRC5 to initiate inflammatory cell death or PANoptosis.

Co-first author Dr. Balamurugan Sundaram of the St. Jude Department of Immunology stated that their screening tests revealed for the first time the role of NLRC5 in our innate immune system’s response to hemolysis, which commonly occurs with cancers, inflammatory diseases, or during infections.

The team also discovered that NAD levels are crucial in regulating NLRC5. Specifically, depleted or low levels of NAD signal NLRC5 to trigger PANoptosis. This finding is significant as it could lead to the development of new therapeutics for infections, cancers, inflammation, and aging.

“By supplementing with the NAD precursor, nicotinamide, we reduced NLRC5 protein expression and PANoptosis. Therapeutically, nicotinamide has been widely studied as a nutrient supplement, and our findings suggest it could be helpful in treating inflammatory diseases,” said Dr. Nagakannan Pandian of St. Jude Department of Immunology and the co-first author of the study.

Read the full article here to learn more about NLRC5 and the study’s significance in developing targeted therapies.

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