{"doi":"10.1111/imr.70008","title":"Innate Immune Sensors in Health and Disease","abstract":"The immune system constantly patrols the body, identifying and responding to deviations from homeostasis. These deviations can include pathogens, foreign substances (such as inert particles or allergens), or signs of host tissue damage (e.g., from trauma or radiation). A robust host response is essential to resolve these challenges. Both immune and nonimmune cells work together to initiate these critical responses. All cells express a variety of pattern recognition receptors (PRRs) that detect potential threats. These PRRs recognize molecular patterns associated with pathogens, known as pathogen-associated molecular patterns (PAMPs), or molecular patterns derived from damaged host tissue, known as damage-associated molecular patterns (DAMPs) (Figure 1). One of the major classes of pattern recognition receptors (PRRs) includes membrane-bound Toll-like receptors (TLRs). As membrane-bound receptors, TLRs recognize extracellular threats, including PAMPs and DAMPs present in the extracellular milieu or within endosomes. Humans possess 10 functional TLRs, designated TLR1 to TLR10 [1]. In contrast, mice—the most used model system in research—have twelve functional TLRs, including TLR1 to TLR9 and then TLR11 to TLR13 [1]. Similarly, C-type lectin receptors (CLRs) [2] and formyl peptide receptors (FPRs) [3] are membrane-bound PRRs that recognize distinct extracellular PAMPs and DAMPs. Collectively, these membrane-bound PRRs initiate signaling pathways, including nuclear factor kappa B (NFκB), mitogen-activated protein kinases (MAPK) and interferon (IFN) signaling. This activation ultimately leads to the production of pro-inflammatory cytokines and promotes a protective immune response. While membrane-bound PRRs effectively detect extracellular PAMPs and DAMPs, they are less suited for sensing intracellular threats. Many pathogens—including viruses, bacteria, and protozoa—have evolved to survive within intracellular niches. Additionally, cellular damage within the intracellular milieu (i.e., damage of organelles) must also be detected, a task that membrane-bound PRRs cannot perform. Fortunately, immune cells are equipped with a diverse array of cytoplasmic PRRs to detect intracellular PAMPs and DAMPs. These cytoplasmic sensors can be broadly classified into three major groups: Nod-like receptors (NLRs), AIM2-like receptors (ALRs) and RIG-I-like receptors (RLRs). Additionally, broad classes of RNA and DNA sensors—including DEAD/H-box helicases and ZBP1—play crucial roles in intracellular immune surveillance. These have been reviewed in this issue and will be discussed in brief below. The innate immune response is a double-edged sword. An insufficient immune response can result in uncontrolled infections and impaired tissue repair, whereas an overactive or dysregulated immune response can lead to autoinflammation and immunopathology. Our understanding of the roles of cytoplasmic PRRs in health and disease continues to evolve. In this review, we compile and summarize current knowledge on various innate immune sensors in different infections and disease conditions. In particular, we highlight the role of the NLRP3 inflammasome in multiple pathological contexts, which will be briefly discussed in the following sections. Cytoplasmic sensors are unique in that some members of this group can assemble into a multiprotein complex known as the inflammasome. The term inflammasome—coined by Dr. Jürg Tschopp—refers to a multimeric protein complex composed of a cytoplasmic PRR, the adaptor protein ASC, and the cysteine protease caspase-1 [4]. Extensive research in this field has now identified exceptions to this classical composition. For instance, CARD-containing PRRs can bypass the requirement for ASC in certain settings (e.g., The NLRC4 inflammasome) [5], while caspase-11 (and caspase-4/−5 in humans) can substitute for caspase-1 in noncanonical inflammasomes [6]. Several inflammasomes have been extensively studied, including NLRP1, NLRP3, NLRC4, AI","journal":"Immunological Reviews","year":2025,"id":522748,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9532,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":444103,"name":"Prajwal Gurung","orcid":"0000-0002-7451-9433","position":0,"is_corresponding":true}],"reference_count":30,"raw_metadata":null,"created_at":"2026-07-19T02:49:58.707747Z","pmid":"39963855","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":[]}