Pathogen recognition and inflammatory signaling in innate immune defenses

Abstract

The innate immune system constitutes the first line of defense against invading microbial pathogens and relies on a large family of pattern recognition receptors (PRRs), which detect distinct evolutionarily conserved structures on pathogens, termed pathogen-associated molecular patterns (PAMPs). Among the PRRs, the Toll-like receptors have been studied most extensively. Upon PAMP engagement, PRRs trigger intracellular signaling cascades ultimately culminating in the expression of a variety of proinflammatory molecules, which together orchestrate the early host response to infection, and also is a prerequisite for the subsequent activation and shaping of adaptive immunity. In order to avoid immunopathology, this system is tightly regulated by a number of endogenous molecules that limit the magnitude and duration of the inflammatory response. Moreover, pathogenic microbes have developed sophisticated molecular strategies to subvert host defenses by interfering with molecules involved in inflammatory signaling. This review presents current knowledge on pathogen recognition through different families of PRRs and the increasingly complex signaling pathways responsible for activation of an inflammatory and antimicrobial response. Moreover, medical implications are discussed, including the role of PRRs in primary immunodeficiencies and in the pathogenesis of infectious and autoimmune diseases, as well as the possibilities for translation into clinical and therapeutic applications.

FIG. 1.

Principles in innate immune recognition by PRRs. During microbial infection or breakdown of tolerance, pathogen-specific molecules, aberrant localization of foreign or self molecules, or abnormal molecular complexes are recognized by PRRs. This event triggers PRR-mediated signaling and induction of an innate immune response, which ultimately results in resolution of infection but also may cause inflammatory diseases or autoimmunity.

FIG. 2.

Cellular PRRs. TLRs are membrane-bound receptors localized at the cellular or endosomal membranes, recognizing PAMPs via the LRR domain and transducing signals to the intracellular environment through the TIR domain. RLRs with a C-terminal helicase domain bind RNA and become activated to transduce CARD-dependent signaling. The dsRNA-activated kinase PKR is an intracellular PRR that senses RNA through binding to two N-terminal dsRNA-binding domains. DAI and AIM2 are intracellular DNA sensors. NLRs are a class of intracellular proteins characterized by a central NOD domain and a C-terminal LRR domain, the latter of which serves as a pattern recognition domain. Signals are transduced through N-terminal domains, including CARD and pyrin (PYD) domains.

FIG. 3.

Recognition of PAMPs from different classes of microbial pathogens. Viruses, bacteria, fungi, and protozoa display several different PAMPs, some of which are shared between different classes of pathogens. Major PAMPs are nucleic acids, including DNA, dsRNA, ssRNA, and 5′-triphosphate RNA, as well as surface glycoproteins (GP), lipoproteins (LP), and membrane components (peptidoglycans [PG], lipoteichoic acid [LTA], LPS, and GPI anchors). These PAMPs are recognized by different families of PRRs.

FIG. 4.

TLRs and TIR domain-containing adaptor molecules. TLR1/2 and TLR2/6 utilize MyD88 and Mal as adaptors. TLR3 is dependent on TRIF for signaling. In the case of TLR4, four different adaptors, i.e., MyD88, Mal, TRIF, and TRAM, are involved, whereas TLR5, -7, -8, and -9 utilize only MyD88. The fifth adaptor, SARM, negatively regulates TRIF-dependent signaling. Overall, MyD88-dependent signaling induces proinflammatory cytokine production, whereas TRIF-dependent signaling stimulates a type I IFN response. In pDCs, stimulation of TLR7 or TLR9 induces type I IFN production by a mechanism dependent on MyD88. See text for further details.

FIG. 5.

Principles in TLR signaling. TLR4 activates both the MyD88-dependent and MyD88-independent, TRIF-dependent pathways. The MyD88-dependent pathway is responsible for early-phase NF-κB and MAPK activation, which control the induction of proinflammatory cytokines. The MyD88-independent, TRIF-dependent pathway activates IRF3, which is required for the induction of IFN-β- and IFN-inducible genes. In addition, this pathway mediates late-phase NF-κB as well as MAPK activation, also contributing to inflammatory responses.

FIG. 6.

Intracellular RNA recognition and signaling. Cytosolic dsRNA or 5′-triphosphate ssRNA is recognized primarily by the cytoplasmic RNA helicases RIG-I and MDA5, which mediate interaction with the adaptor IPS-1, localized to mitochondria, and trigger signaling to NF-κB and IRF3 via IKK and TBK/IKKɛ, respectively. dsRNA can also be recognized by TLR3 localized in the endosomal compartment or by cytosolic PKR, but whereas TLR3 triggers signaling to NF-κB and IRF3, PKR instead activates NF-κB and MAPKs. Finally, ssRNA is recognized by TLR7/8 in endosomes and induces signaling to IRF7 as well as to NF-κB and MAPKs (not shown in the figure).

FIG. 7.

Negative regulation of PRR signaling. Signaling through PRRs is negatively regulated by endogenous and microbial proteins. Endogenous negative control of PRR signaling (molecules depicted in red) serves the purpose of mediating negative feedback on the inflammatory response, whereas microbial interference with PRRs (viral molecules shown in green) constitutes a means to evade the host antimicrobial response. See text for further details.