NOD-like Receptors (NLRs) are a large family of intracellular proteins that consist of a N-terminal protein interaction domain (PYD, CARD or BID), followed by a central Nucleotide-binding and Oligomerization Domain (NOD/NATCH) and a C-terminus characterized by a Leucine-rich Repeat domain (LRR). Although NLRs are structurally homologous to each other, they perform a diverse array of cellular functions and play key roles in the regulation of innate immune responses. NLRs are not only expressed in immune cells such as macrophages, dendritic cells and neutrophils, but are also expressed in non-immune cells such as epithelial cells. Some NLRs (NLRP1, NLRP3, NLRP9b, NLRC4) are activated in response to cell stress or pathogen associated molecular patterns (PAMPs) and form a macromolecular complex termed the inflammasome, containing inflammatory caspases (Caspase-1 and -11), which activate proinflammatory cytokines and induce pyroptotic cell death. Certain NLR family members, such as NOD1 and NOD2, detect PAMPs in the cytoplasm and initiate kinase signaling cascades that activate transcription factors, which subsequently mediate the synthesis of cytokines and other mediators of inflammation. Other NLR family members act directly as transcriptional activators (NRLC5 and CIITA) leading to the expression of Major Histocompatibility Complex-I (MHC-I) and MHC-II, respectively. Another group of NLRs (NLRP6, NLRP12, NLRX1) appear to suppress or modulate inflammation by altering immune signaling pathways including TLRs and NF-ƙB. Finally, NLRP2, NLRP5 and NLRP7 are involved in fetal development without any clear connection to immunoregulation.

Mutations or polymorphisms in NLRs have been associated with increased susceptibility to various pathologies including (i) infectious disease; (ii) autoimmunity and autoinflammation, (iii) cancer development and progression and (iv) heart disease. Although some NLRs are well-studied, many aspects of NLR research remain poorly investigated. Extensive research has been performed on NLRP3, yet we still lack a complete understanding of how cellular damage and PAMPs activate this sensor. NLRP9b was only recently described as a cytoplasmic RNA sensor in intestinal epithelial cells leading to inflammasome activation. Furthermore, NLRP4 and NLRP8, remain to be studied in detail.

This Research Topic will provide a forum for articles addressing (i) the structure, function and activation mechanisms of NLRs in the immune system; (ii) regulation of NLR signaling pathways in immunity and (ii) their functions in immune-related diseases. We particularly welcome the submission of Reviews, Mini-Reviews, Original Research, Perspective and Commentary articles that cover, but are not limited to, the following sub-topics:

1. Structural analysis of NLRs in the context of the immune system.
2. NLR protein-protein interactions from an immunological perspective.
3. Post-translational regulation/modification of NLRs and their signaling pathways in innate immunity.
4. Transcriptional regulation of NLR genes in immune cells and their association with immunological diseases.
5. Mutations/polymorphisms in NLR genes associated with infectious, autoimmune, and autoinflammatory diseases.
6. Role of NLRs in infectious and immune-related diseases.
7. Therapeutic targeting of NLRs and their signaling pathways for the treatment of infectious and immunological diseases.
8. Immunological roles of under-studied NLRs (e.g. NLRP4, NLRP5, NLRP8, etc.)
9. Novel research/perspectives on NLR activation mechanisms and downstream signaling and their involvement in innate immunity.

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Frontiers in Immunology

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