The innate immune system safeguards the human body from potential diseases and infections, relying on specialized sensors to detect and communicate threats. Among these, cell death is a crucial defense strategy. Recent research from St. Jude Children’s Research Hospital has unveiled NLRC5 as a previously unknown innate immune sensor that triggers cell death. Published in Cell, the study elucidates NLRC5’s role in driving PANoptosis, a significant form of inflammatory cell death, with implications for therapeutic developments targeting NLRC5 against infections, inflammatory disorders, and aging.
In response to various threats, innate immune sensors can form complexes like inflammasomes or PANoptosomes. While inflammasomes act swiftly akin to an emergency broadcast system, PANoptosomes integrate diverse signals and components for a more comprehensive response. The activation triggers for innate immune sensors, a longstanding mystery, have been under investigation for decades.
Nucleotide-binding oligomerization domain-like receptors (NLRs) are crucial in inflammatory signaling, functioning as sensors that detect threats. Despite their importance, the specific roles of many NLRs remain unclear. Scientists at St. Jude conducted an extensive screen focused on NLRC5, discovering that depletion of nicotinamide adenine dinucleotide (NAD), vital for energy production, induces NLRC5-mediated cell death via PANoptosis.
“Understanding what various members of the NLR family sense and their functions is a key question in immunology and innate immunity,” noted corresponding author Thirumala-Devi Kanneganti, Ph.D., Vice Chair of the Department of Immunology at St. Jude. “NLRC5, once enigmatic, now stands revealed as an innate immune sensor and regulator of cell death, driving inflammatory PANoptosis through complex formation.”
The research team rigorously screened pathogens, pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), and cytokines to pinpoint NLRC5 triggers. They identified that combinations involving heme, released during hemolysis in infections and diseases, specifically induce NLRC5-dependent inflammatory cell death, PANoptosis.
Further investigations into NLRC5 regulation revealed that its protein expression is governed by NAD levels. Depletion of NAD signals a threat to the immune system, triggering PANoptosis through NLRC5 activation. “Supplementing with nicotinamide, an NAD precursor, reduced NLRC5 expression and PANoptosis,” explained co-first author Nagakannan Pandian, Ph.D., from St. Jude’s Department of Immunology, suggesting therapeutic potential in treating inflammatory diseases.
Additionally, the researchers uncovered NLRC5’s involvement in an NLR network with NLRP12, forming an NLRC5-PANoptosome complex that initiates inflammatory cell death. This finding builds on previous studies by the Kanneganti lab, highlighting NLRP12’s role in PANoptosis.
Given their association with infection, inflammation, cancer, and aging, NLRs present promising targets for therapeutic development. Deleting Nlrc5 in experimental models protected against inflammatory cell death and disease progression, underscoring NLRC5’s potential as a therapeutic target.
“The foundational insights gained into innate immune sensing can inform treatments for diverse diseases and conditions,” added Kanneganti. “From aging to infectious and inflammatory disorders lacking targeted therapies, NLRC5-targeted strategies offer promising avenues.”
Authors contributing to this study include Emily Alonzo from Cell Signaling Technology’s Department of Research and Development, along with Hee Jin Kim, Hadia Abdelaal, Omkar Indari, Roman Sarkar, Rebecca Tweedell, Jonathan Klein, Shondra Pruett-Miller, and Peter Vogel from St. Jude, as well as Raghvendra Mall, formerly of St. Jude and now affiliated with the Technology Innovation Institute in Abu Dhabi.
