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NLRX1 is a member of the of the Nod-like receptor (NLR) family, and it represents a unique pattern recognition molecule (PRM) as it localizes to the mitochondrial matrix in resting conditions. Over the past fifteen years, NLRX1 has been proposed to regulate multiple cellular processes, including antiviral immunity, apoptosis, reactive oxygen species (ROS) generation and mitochondrial metabolism. Similarly, in vivo models have shown that NLRX1 was associated with the control of a number of diseases, including multiple sclerosis, colorectal cancer and ischemia-reperfusion injury. This apparent versatility in function hinted that a common and general overarching role for NLRX1 may exist. Recent evidence has suggested that NLRX1 controls mitophagy through the detection of a specific “danger signal”, namely the defective import of proteins into mitochondria, or mitochondrial protein import stress (MPIS). In this review article, we propose that mitophagy regulation may represent the overarching process detected by NLRX1, which could in turn impact on a number of diseases if dysfunctional.

It has long been appreciated that cues from the innate immune system orchestrate downstream adaptive immune responses. Although previous work has focused on the roles of Toll-like receptors in this regard, relatively little is known about how Nod-like receptors instruct adaptive immunity. Here we review the functions of different members of the Nod-like receptor family in orchestrating effector and anamnestic adaptive immune responses. In particular, we address the ways in which inflammasome and non-inflammasome members of this family affect adaptive immunity under various infectious and environmental contexts. Furthermore, we identify several key mechanistic questions that studies in this field have left unaddressed. Our aim is to provide a framework through which immunologists in the adaptive immune field may view their questions through an innate-immune lens and vice-versa.

Nod-like receptors (NLRs) are innate immune receptors that play a key role in sensing components from pathogens and from damaged cells or organelles. NLRs form signaling complexes that can lead to activation of transcription factors or effector caspases – by means of inflammasome activation –Inflammatory arthritis (IA) culminating in promoting inflammation. An increasing body of research supports the role of NLRs in driving pathogenesis of IA, a collection of diseases that include rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis, and pediatric arthritis. In this review, we briefly discuss the main drivers of IA diseases and dive into the evidence for – and against – various NLRs in driving these diseases. We also review the studies examining the use of NLR and inflammasome inhibitors as potential therapies for IA.

The mammalian intestinal tract is the largest immune organ in the body and comprises cells from non-hemopoietic (epithelia, Paneth cells, goblet cells) and hemopoietic (macrophages, dendritic cells, T-cells) origin, and is also a dwelling for trillions of microbes collectively known as the microbiota. The homeostasis of this large microbial biomass is prerequisite to maintain host health by maximizing beneficial symbiotic relationships and minimizing the risks of living in such close proximity. Both microbiota and host immune system communicate with each other to mutually maintain homeostasis in what could be called a "love-hate relationship." Further, the host innate and adaptive immune arms of the immune system cooperate and compensate each other to maintain the equilibrium of a highly complex gut ecosystem in a stable and stringent fashion. Any imbalance due to innate or adaptive immune deficiency or aberrant immune response may lead to dysbiosis and low-grade to robust gut inflammation, finally resulting in metabolic diseases.

The elaboration of an effective immune response against pathogenic microbes such as viruses, intracellular bacteria or protozoan parasites relies on the recognition of microbial products called pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs). Ligation of the PRRs leads to synthesis and secretion of pro-inflammatory cytokines and chemokines. Infected cells and other stressed cells also release host-cell derived molecules, called damage-associated molecular patterns (DAMPs, danger signals, or alarmins), which are generic markers for damage. DAMPs are recognized by specific receptors on both immune and nonimmune cells, which, depending on the target cell and the cellular context, can lead to cell differentiation or cell death, and either inflammation or inhibition of inflammation. Recent research has revealed that DAMPs and PAMPs synergize to permit secretion of pro-inflammatory cytokines such as interleukin-1β (IL-1β): PAMPs stimulate synthesis of pro-IL-1β, but not its secretion; while DAMPs can stimulate assembly of an inflammasome containing, usually, a Nod-like receptor (NLR) member, and activation of the protease caspase-1, which cleaves pro-IL-1β into IL-1β, allowing its secretion. Other NLR members do not participate in formation of inflammasomes but play other essential roles in regulation of the innate immune response.