Unsolved Mysteries in NLR Biology

Abstract

NOD-like receptors (NLRs) are a class of cytoplasmic pattern-recognition receptors. Although most NLRs play some role in immunity, their functions range from regulating antigen presentation (NLRC5, CIITA) to pathogen/damage sensing (NLRP1, NLRP3, NLRC1/2, NLRC4) to suppression or modulation of inflammation (NLRC3, NLRP6, NLRP12, NLRX1). However, NLRP2, NLRP5, and NLRP7 are also involved in non-immune pathways such as embryonic development. In this review, we highlight some of the least well-understood aspects of NLRs, including the mechanisms by which they sense pathogens or damage. NLRP3 recognizes a diverse range of stimuli and numerous publications have presented potential unifying models for NLRP3 activation, but no single mechanism proposed thus far appears to account for all possible NLRP3 activators. Additionally, NLRC3, NLRP6, and NLRP12 inhibit NF-κB activation, but whether direct ligand sensing is a requirement for this function is not known. Herein, we review the various mechanisms of sensing and activation proposed for NLRP3 and other inflammasome activators. We also discuss the role of NLRC3, NLRP6, NLRP12, and NLRX1 as inhibitors and how they are activated and function in their roles to limit inflammation. Finally, we present an overview of the emerging roles that NLRP2, NLRP5, and NLRP7 play during embryonic development and postulate on the potential pathways involved.

Keywords: DAMPs; NOD-like receptors; PAMPs; caspase-1; embryonic development; inflammasomes; innate immunity.

Figure 1

Unsolved mysteries in NLRP3 biology. Q1: Is there a common DAMP that activates NLRP3? Do DAMPs directly activate NLRP3? Do DAMPs induce structural rearrangement of NLRP3? Q2: How do post-translational modifications regulate activation on a structural level? Q3: Is mitochondrial localization essential for NLRP3 inflammasome formation? Q4: How does autophagy inhibit NLRP3? Does autophagy directly engulf NLRP3 inflammasomes? Does it engulf damaged mitochondria where NLRP3 is localized? Does autophagy merely remove the source of DAMPs? Q5: Are there additional upstream sensors or adaptors that facilitate NLRP3 activation?

Figure 2

Mechanisms of inhibitory NLRs. Q1: How do inhibitory NLRs function? Is PAMP recognition required for inhibitory NLR function? Is NLR expression sufficient for inhibitory function? Q2: Is NLRX1 an inhibitor of MAVS or a modulator of mitochondrial ROS? Q3: How does NLRX1 inhibit NF-κB if it is localized to the mitochondria? Q4: Do NLRP6 and NLRP12 regulate inflammasome activation and how? Does gut flora play a role in inflammasome activation in the absence of NLRP6 and NLRP12. Q5: Why are there so many inhibitory NLRs? Do inhibitory NLRs play redundant or context specific roles?