REVIEW NOX enzymes and Toll-like receptor signaling Eric Ogier-Denis & Sanae Ben Mkaddem & Alain Vandewalle Received: 30 January 2008 / Accepted: 24 April 2008 / Published online: 21 May 2008 # Springer-Verlag 2008 Abstract Invading microorganisms are recognized by the host innate immune system through pattern recognition receptors. Among these receptors, Toll-like receptors (TLRs) are able to sense the molecular signatures of microbial pathogens, protozoa, fungi, and virus and activate proinflammatory signaling cascades. In addition to their role in bacterial killing by phagocytes, reactive oxygen species generated by NADPH oxidase (NOX) homologues also play key roles in signaling and host defense in a variety of cell types. Recent studies have demonstrated a link between TLR activation and NOX homologues following microbial recognition highlighting their impor- tant role in the innate immune response and host defense. Keywords NADPH oxidases . Reactive oxygen species . Toll-like receptors . Innate immunity . Host defense The innate immune system uses a wide variety of microbial recognition receptors including Toll-like receptors (TLRs), lectins, scavenger receptors, and integrins to identify potential pathogens. Members of the TLR family primarily function in recognizing a plethora of microbial structures referred to as pathogen-associated molecular patterns (PAMPs) including molecules from Gram-positive and Gram-negative bacteria, DNA and RNA virus, fungi, and protozoa [73]. TLRs are essential for the immediate detection and control of infection in mammals and lead to a series of signaling events resulting in proinflammatory gene expression and acute host response necessary to kill the pathogens [2, 99, 100]. TLRs are type I transmembrane proteins of the interleukin-1 receptor family that possess an N-terminal leucin-rich-repeat domain for ligand binding and a C-terminal intracellular signaling domain (TIR) [66, 72]. To date, 13 mammalian TLRs, ten in humans, and 13 in mice have been identified, although not all have been assigned a specific ligand [20, 73, 114]. TLRs1–9 are conserved among humans and mice while TLR10 and TLR11 are functional only in humans or in mice, respectively. TLR2 is involved in the recognition of a wide range of microbial lipopeptides and generally functions as an heterodimer with either TLR1 or TLR6 to distinguish subtle differences between triacetylated and diacetylated lipoproteins [101, 102]. TLR3 is involved in the recogni- tion of viral double-strand RNA and activates NF-κB and interferon regulatory factor 3 (IRF3) leading to the production of antiviral molecules, such as interferon (IFN)-α/ β [3]. TLR4 recognizes lipopolysaccharides (LPS) from Gram-negative bacteria [91], and TLR5 is involved in the recognition of bacterial flagellin [41]. TLR7 and TLR8 bind viral single-strand RNA [43]. Lastly, TLR9 recognizes bacterial DNA containing CpG motifs [44]. In addition to detecting PAMPs, TLR2 and TLR4 also interact with multiple other endogenous molecules including hya- luronic acid [104], fibrinogen [97], reactive oxygen species (ROS) [31], proteins released from dead or dying cells such as high-mobility group box 1 (HMGB1) [85], and heat shock proteins [108]. The engagement of TLRs by microbial components triggers the activation of signaling cascades, leading to the induction of genes involved in antimicrobial host defense. Semin Immunopathol (2008) 30:291–300 DOI 10.1007/s00281-008-0120-9 E. Ogier-Denis : S. B. Mkaddem : A. Vandewalle INSERM, U773, Centre de Recherche Biomédicale Bichat Beaujon, CRB3, BP 416, 75018 Paris, France E. Ogier-Denis (*) : S. B. Mkaddem : A. Vandewalle Université Paris 7-Denis Diderot, site Bichat, BP 416, 75870 Paris, France e-mail: ogier@bichat.inserm.fr