{"doi":"10.1111/imr.12912","title":"Intracellular innate immune receptors: Life inside the cell","abstract":"The innate immune system is the critical first line of defense against infectious and sterile insults. A cell’s ability to sense these insults relies on a series of germline-encoded receptors, generally referred to as pattern recognition receptors (PRRs). PRRs are responsible for recognizing unique molecular patterns from microbes known as pathogen-associated molecular patterns (PAMPs) and endogenous molecules released from damaged and dying cells known as damage-associated molecular patterns (DAMPs). There are several different PRRs found throughout the cell, including Toll-like receptors (TLRs), C-type lectin receptors (CLRs), nucleotide-binding domain, leucine-rich repeat-containing (or NOD-like) receptors (NLRs), absent in melanoma 2 (AIM2), IFI16, pyrin, Z-DNA-binding protein 1 (ZBP1), retinoic acid-inducible gene I (RIG-I), MDA5, and many more. PRRs can be found on the membrane, in the cytosol, and in the nucleus. Some PRRs can induce the formation of a multiprotein complex called the inflammasome that leads to the processing and release of the proinflammatory cytokines IL-1β and IL-18 and cell death in the form of pyroptosis. Within the NLR family of PRRs, there are some proteins that form an inflammasome, such as NLRP1, NLRP3, and NLRC4, and some that do not, such as NLRC1 and NLRC2 (NOD1 and NOD2). AIM2 and pyrin are also well-established as sensors that form an inflammasome. Whether they form inflammasomes or not, PRRs are each important for sensing their respective ligands and initiating signaling pathways that drive gene expression, protein production, cytokine and chemokine release, and cell death while also shaping the adaptive immune response, dictating the overall fitness of the immune system. Within the cell, membrane-bound PRRs are responsible for sensing external insults, while intracellular cytosolic and nuclear PRRs are essential for detecting intracellular pathogens or alterations in cellular homeostasis. In this issue of Immunological Reviews, we explore the intracellular innate immune receptors, characterizing their sensing and signaling pathways and detailing their diverse roles in health and disease. We also describe the therapeutic implications of modulating these pathways. Downstream of PRR sensing of PAMPs and DAMPs, several signaling cascades are initiated (Figure 1). These pathways lead to proinflammatory cytokine and chemokine secretion and cell death, among other outcomes. Among the intracellular PRRs, some have the ability to form a multiprotein complex known as the inflammasome. NLRP1, NLRP3, NLRC4, AIM2, and pyrin are well-characterized to form inflammasomes, while several other receptors have also been recognized to form an inflammasome in context-dependent manners. The inflammasome is typically composed of a sensor, the adaptor protein ASC, and the effector protein caspase-1. Inflammasome assembly provides the platform for autocatalytic cleavage and activation of caspase-1. Activated caspase-1 can then go on to cleave pro–IL-1β and pro–IL-18 into their active forms and gasdermin D to release its N-terminus. The gasdermin D N-terminus forms pores in the membrane to execute an inflammatory form of cell death known as pyroptosis and allows the release of IL-1β and IL-18, along with other cellular contents. NLRP1 (NLR family, pyrin domain-containing 1) was the first PRR to be identified to form an inflammasome,1 although much about its biology has remained unclear since that discovery in 2002. NLRP1 is unique among the NLRs in that it contains a C-terminal function-to-find (FIIND) domain that undergoes autoproteolysis before inflammasome activation. This produces two fragments that remain associated, preventing inflammasome formation until an additional stimulus is received. Recently, it has been shown that NLRP1 is activated in response to the Bacillus anthracis lethal toxin and Toxoplasma gondii, among other stimuli. NLRP1 activation requires the stimulus to induce proteasome-mediated degrad","journal":"Immunological Reviews","year":2020,"id":52990,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":124,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9527,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":105446,"name":"Thirumala‐Devi Kanneganti","orcid":"0000-0002-6395-6443","position":0,"is_corresponding":true}],"reference_count":60,"raw_metadata":null,"created_at":"2026-07-18T20:44:25.349797Z","pmid":"32856334","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}