Biology: The Innate Immune System

The innate immune system is referred to as the first line in host defense against invading pathogens and preserve host integrity [1]. Of them the innate immune cells have sensors such as macrophages and dendritic cells (DCs) detect molecular components of foreign microorgan¬isms known as pathogen-associated molecule patterns (PAMPs) through PRRs. Its highly developed ability to recognize microbial patterns and host derived danger signals relies on so-called PRRs, especially on the TLRs, RLRs and NLRs (Fig. 1).

Ligation of TLRs by PAMPs induces a set of intracellular signaling molecules, leading to the expression of NF κB dependent pro-inflammatory cytokines or IRF dependent type I interferons (IFNs). RLRs, which are cytoplasmic RNA helicases,
including retinoic acid-inducible gene I (RIG-I), melanoma differentiation-associated protein 5 (MDA5), and laboratory of genetics and physiology gene 2 (LGP2), that are essential for innate recognition of viruses, control of viral replication and dissemination through the production of type I IFNs.
NLRs consist of a large group of intracellular PRRs, such as nucleotide binding oligomerization domain proteins (NODs), and leucine rich repeat (LRR) and NOD-like receptor family pyrin domains (NLRPs), which are crucial for host defense against bacterial infection [2]. In addition, other molecules or complexes have been recently discovered to sense cellular RNA or DNA and induce IFN production. Despite the crucial role of innate signaling in host defense, a systematic but flexible regulatory network is required to ensure an appropriate outcome of PRR signaling and to efficiently eliminate invading pathogens while avoiding harmful immunopathology. In this regard, many regulators such as phosphatases and kinases, ubiquitin-related proteins, transcription fac¬tors and epigenetic molecules are involved in the modulation of PRR signaling by targeting distinct steps of the signaling cascade. Recent studies have revealed that host cells respond to intracellular dsDNA released by DNA viruses, bacteria, or host dying cells to trigger type I IFN induction, which occurs through a TLR and RLR-independent mechanism [3]. In addition, the signals down¬stream of TLRs, RLRs and NLRs are cross modulated
in either a cooperative or an antagonistic manner. In this review, we focus on the recognition mechanisms and signaling pathways modulator of TLR, RLR and NLR under biological and/or pathological conditions, and their function in antiviral, anti-inflammatory, and anti-cancer responses. Of these small molecules, those that have under¬gone rapid advancement or substantial breakthroughs in recent years are discussed in detail, and those that have been widely and extensively studied or reviewed are briefly mentioned