Toll-like receptors (TLRs) and innate immunity Satoshi Uematsu · Shizuo Akira Received: 10 April 2006 / Accepted: 8 June 2006 / Published online: 10 August 2006 © Springer-Verlag 2006 Abstract The innate immune system is an evolutionally conserved host defense mechanism against pathogens. Innate immune responses are initiated by pattern recognition receptors (PRRs), which recognize specific structures of microorganisms. Among them, Toll-like receptors (TLRs) are capable of sensing organisms ranging from bacteria to fungi, protozoa, and viruses, and play a major role in innate immunity. However, TLRs recognize pathogens either on the cell surface or in the lysosome/endosome compartment. Recently, cytoplasmic PRRs have been identified to detect pathogens that have invaded cytosols. In this review, we focus on the functions of PRRs in innate immunity and their downstream signaling cascades. Keywords TLR · NLR · RIG-I Introduction The innate immune response is the first line of defense against microbial infections. Since the discovery of the Drosophila protein Toll, which induces effective immune responses to Aspergillus fumigatus, accumulating evidence showed that the innate immune system specifically recognizes invading microorganisms. The targets of innate immune recognition are the conserved molecular patterns (pathogen-associated molecular patterns, PAMPs) of microorganisms. Receptors in innate immunity are therefore called pattern recognition receptors (PRRs). PAMPs are generated by microbes and not by the host, suggesting that PAMPs are good targets for innate immunity to discriminate between self- and nonself. Furthermore, PAMPs are essential for microbial survival and are conserved structures among many pathogens, which allows innate immunity to recognize microorganisms with limited numbers of PRRs. Among PRRs, Toll-like receptors (TLRs), mammalian homologs of Toll, were highlighted as the key recognition structures of the innate immune system in the past few years. TLRs are capable of sensing organisms ranging from bacteria to fungi, protozoa, and viruses. However, host recognition and response is not restricted to TLRs. Some members of the NACHT (domain present in NAIP, CIITA, HET-E, and TP1)-LRR (leucine-rich repeat) (NLR) family, which includes both nucleotide-binding oligomerization domain (NOD) proteins and NACHT-LRR- and pyrin-domain-containing proteins (NALPs), recognize microbial components in the cytosol. Furthermore, the RNA helicase, retinoic acid inducible gene-I (RIG-I), was identified as a cytosolic receptor for intracellular double-stranded (dsRNA) and induces type I interferons (IFNs)Toll-like receptors (TLRs) and innate immunity Satoshi Uematsu · Shizuo Akira Received: 10 April 2006 / Accepted: 8 June 2006 / Published online: 10 August 2006 © Springer-Verlag 2006 Abstract The innate immune system is an evolutionally conserved host defense mechanism against pathogens. Innate immune responses are initiated by pattern recognition receptors (PRRs), which recognize specific structures of microorganisms. Among them, Toll-like receptors (TLRs) are capable of sensing organisms ranging from bacteria to fungi, protozoa, and viruses, and play a major role in innate immunity. However, TLRs recognize pathogens either on the cell surface or in the lysosome/endosome compartment. Recently, cytoplasmic PRRs have been identified to detect pathogens that have invaded cytosols. In this review, we focus on the functions of PRRs in innate immunity and their downstream signaling cascades. Keywords TLR · NLR · RIG-I Introduction The innate immune response is the first line of defense against microbial infections. Since the discovery of the Drosophila protein Toll, which induces effective immune responses to Aspergillus fumigatus, accumulating evidence showed that the innate immune system specifically recognizes invading microorganisms. The targets of innate immune recognition are the conserved molecular patterns (pathogen-associated molecular patterns, PAMPs) of microorganisms. Receptors in innate immunity are therefore called pattern recognition receptors (PRRs). PAMPs are generated by microbes and not by the host, suggesting that PAMPs are good targets for innate immunity to discriminate between self- and nonself. Furthermore, PAMPs are essential for microbial survival and are conserved structures among many pathogens, which allows innate immunity to recognize microorganisms with limited numbers of PRRs. Among PRRs, Toll-like receptors (TLRs), mammalian homologs of Toll, were highlighted as the key recognition structures of the innate immune system in the past few years. TLRs are capable of sensing organisms ranging from bacteria to fungi, protozoa, and viruses. However, host recognition and response is not restricted to TLRs. Some members of the NACHT (domain present in NAIP, CIITA, HET-E, and TP1)-LRR (leucine-rich repeat) (NLR) family, which includes both nucleotide-binding oligomerization domain (NOD) proteins and NACHT-LRR- and pyrin-domain-containing proteins (NALPs), recognize microbial components in the cytosol. Furthermore, the RNA helicase, retinoic acid inducible gene-I (RIG-I), was identified as a cytosolic receptor for intracellular double-stranded (dsRNA) and induces type I interferons (IFNs)