Abstract
Cytosolic pattern recognition receptors (PRRs) sense a wide range of endogenous danger-associated molecular patterns as well as exogenous pathogen-associated molecular patterns. In particular, Nod-like receptors containing a pyrin domain (PYD), called NLRPs, and AIM2-like receptors (ALRs) have been shown to play a critical role in host defense by facilitating clearance of pathogens and maintaining a healthy gut microflora. NLRPs and ALRs both encode a PYD, which is crucial for relaying signals that result in an efficient innate immune response through activation of several key innate immune signaling pathways. However, mutations in these PRRs have been linked to the development of auto-inflammatory and autoimmune diseases. In addition, they have been implicated in metabolic diseases. In this review, we summarize the function of PYD-containing NLRPs and ALRs and address their contribution to innate immunity, host defense, and immune-linked diseases.
Highlights
The innate immune system relies on germline-encoded pattern recognition receptors (PRRs) to detect threats against tissue homeostasis
While Toll-like receptors (TLRs) utilize their TIR domain and RIGI-like receptors (RLRs) and NLRCs their CARD for downstream signaling upon activation, NLRPs and AIM2-like receptors (ALRs) recruit signaling adaptors through their PYRIN domain (PYD)
Active NLRPs and ALRs trigger multiple innate immune effector pathways, but by far the best established function of these PYDcontaining proteins is the assembly of inflammasomes, which are large multiprotein platforms that form in response to infection and tissue damage and are responsible for the activation of inflammatory caspases, in particular caspase-1 [1, 2]
Summary
The innate immune system relies on germline-encoded pattern recognition receptors (PRRs) to detect threats against tissue homeostasis. In agreement with in vitro data showing that NLRP12 antagonizes NF-κB signaling pathways, NLRP12−/− mice were more susceptible to intestinal inflammation, colitis and the associated colorectal tumorigenesis, due to a failure to resolve proinflammatory non-canonical NF-κB, ERK, and AKT signaling, which resulted in elevated levels of pro-inflammatory cytokines and chemokines (Figure 5) Overall, this suggests an important role for NLRP12 in maintaining intestinal homeostasis [166, 167]. Dependent on the context and cell type, NLRP12 either promotes or antagonizes immune and inflammatory responses, which has been observed for several other NLRPs. AIM2-LIKE RECEPTORS The ALRs AIM2 and IFI16 belong to the PYHIN protein family, which is named after their domain architecture, typically consisting of an N-terminal PYD and one or two C-terminal hematopoietic IFN-inducible nuclear protein with 200-amino acids (HIN-200) domains (Figure 1B). There is evidence that hereditary mutations in NLRP1 may lead to excessive inflammasome activation, which is much better understood for NLRP3, as discussed below
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