Innate immunity receptors

3.1. Pattern recognition receptors (PRRs)

The innate immune system is a sophisticated system, which relies on its ability to detect invading microbes, tissue damage or stress through evolutionarily conserved receptors (JANEWAY, 1989; MEDZHITOV; JANEWAY, 2000). It has a large number of well-conserved

microbial structures, which are known as pathogen-associated molecular patterns (PAMPs), recognized by pattern recognition receptors (PRRs) (CARRILLO et al., 2017; JANG et al., 2015; MOGENSEN, 2009). However, these receptors are less numerous than those of the adaptive immune system. The recognition of PAMPs by a PRR activates a signaling pathway leading to an inflammatory response that induces secretion of cytokines and chemokines and, consequently, the activation of an adaptive immune response (CARRILLO et al., 2017; JANG et al., 2015; MOGENSEN, 2009). PRRs are expressed primarily by cells of the innate immune system such as macrophages, monocytes, dendritic cells, and neutrophils. However, other cell types are able to express PRRs example of epithelial cells (JANG et al., 2015).

Historically, the theory that cells of the immune system can detect and respond to all molecular patterns of pathogens has been developed by Charles Janeway (JANEWAY, 1989). However, this model failed to explain how the immune system could distinguish between commensal and pathogenic bacteria. Thus, Matzinger proposed an alternative theory about the innate immune system that said that the system did not distinguish between what is proper (cells of the organism) and what is not itself (agents foreign to the organism), but rather respond to the signs of danger that are emitted by the body's cells, inducing an inflammatory response in response to these danger signals (MATZINGER, 1994; PRADEU; COOPER, 2012).

Currently, four families of PRRs are known to operate cooperatively to recognize endogenous microbial pathogens or endogenous danger signals: toll-like receptor system (TLRs) and C- type lectin receptors (CLRs), which are transmembrane receptors that monitor the extracellular environment, as well as the interior of the endosomes, and the intracellular receptors like [RIG- I-like receptors (RLRs) and nucleotide-binding domain leucine-rich repeats (NLRs)] that act on the cytosol (BAUERNFEIND; HORNUNG, 2013; TEMPLETON; MOEHLE, 2014). Among the transmembrane receptors, the TLRs were first discovered and therefore are the most studied class of receptors (AGIER; PASTWIŃSKA; BRZEZIŃSKA-BŁASZCZYK, 2018; JANG et al., 2015; KAWAI; AKIRA, 2009). TLRs can be expressed in various cell types, such as monocytes, macrophages, B and T lymphocytes, dendritic cells, neutrophils, NK cells, epithelial cells, endothelial cells, and Mast cells. Currently, 10 TLR genes have been identified in humans (TLR1–TLR10) and 12 (TLR1–TLR9, TLR11–TLR13) in mice (GOULOPOULOU;

MCCARTHY; WEBB, 2015; KIELIAN, 2009).

TLRs can be classified according to their cellular location, for example the TLRs located on the plasma membrane are TLR 1, 2, 4, 5, 6, and 11 whereas the TLRs located in the endosomes are TLR 3, 7, 8, 9 and 13 (KAWAI; AKIRA, 2009). Broadly, TLRs can detect signs of danger such as peptides, lipopeptides, glycopeptides, glycolipids and nucleic acids (KAWAI;

AKIRA, 2009). NLR receptors, along with TLRs, cooperate to recognize and respond to pathogens and activate pro and anti-inflammatory mechanisms (CARRILLO et al., 2017).

34 CLRs recognize specific polysaccharides and glycopeptides (ARTIGAS et al., 2017;

WOLFERT; BOONS, 2013). RLRs are cytoplasmic receptors and respond primarily to the presence of RNA viruses and together with the NLRs are cytosolic proteins that probe intracellular microbial molecules and danger signs (RAYMOND et al., 2017).

3.2. NOD-like receptors (NLRs)

NLRs are a family of receptors located on the cytosol that recognize PAMPs. They are pattern recognition receptors that stand out as one of the major receptors involved in regulating the innate immune response. NLRs cooperate along with TLRs and act on the regulation of inflammatory and apoptotic responses, being found in professional phagocytes such as macrophages and dendritic cells and non-professional phagocytes such as epithelial cells (JANG et al., 2015).

The NLRs can be characterized by three structural domains:a leucine-rich repeat (LRR); a central nucleotide-binding domain/NOD (NACHT); and a caspase activation and recruitment domains (CARD), pyrin domain (PYD), or baculovirus inhibitor of apoptosis protein repeat (BIR) (BAUERNFEIND; HORNUNG, 2013). In humans, there are 22 known NLRs characterized by N-terminals composed of five receptor subfamilies, which resulted in the splitting of NLR family members into two main subfamilies: the NLRC - NLR family CARD domain-containing family (NOD1, NOD2, NLRC3, NLRC4 and NLRC5) and NLRP - NACHT, LRR, and the PYD domain-containing family (NLRP1-14), which accompanies three other small subfamilies NLRA (CIITA), NLRB (NAIP – neuronal apoptosis inhibitory protein) and NLRX (NLRX1) (BAUERNFEIND; HORNUNG, 2013) (Fig. 5).

The best characterized NLRs are NOD1 (NLRC1), NOD2 (NLRC2), NLR family containing a CARD domain 4 (NLRC4 - previously known as IPAF), and NLR family pyrin domain containing 3 (NLRP3) (DI VIRGILIO, 2013). Almost two decades ago, research began on the role of NLR receptors as inflammation mediators surrounding the discovery of a multiprotein complex called the inflammasome. This inflammasome is the basis of this work and will be described in the next topic.

Figure 5: Scheme of NLR receptor subfamilies and their structure in humans.

NLRA (CIITA), NLRB (NAIP), NLRC (NOD1, NOD2, NLRC3, NLRC4 and NLRC5), NLRP3 (NLRP1, NLRP2-9, NLRP11-14 and NLRP10) and NLRX (NLRX1). According to (BAUERNFEIND et al., 2011).