Abstract
Uric acid (UA), a product of purine nucleotide degradation able to initiate an immune response, represents a breakpoint in the evolutionary history of humans, when uricase, the enzyme required for UA cleavage, was lost. Despite being inert in human cells, UA in its soluble form (sUA) can increase the level of interleukin-1β (IL-1β) in murine macrophages. We, therefore, hypothesized that the recognition of sUA is achieved by the Naip1-Nlrp3 inflammasome platform. Through structural modelling predictions and transcriptome and functional analyses, we found that murine Naip1 expression in human macrophages induces IL-1β expression, fatty acid production and an inflammation-related response upon sUA stimulation, a process reversed by the pharmacological and genetic inhibition of Nlrp3. Moreover, molecular interaction experiments showed that Naip1 directly recognizes sUA. Accordingly, Naip may be the sUA receptor lost through the human evolutionary process, and a better understanding of its recognition may lead to novel anti-hyperuricaemia therapies.
Highlights
Host responses against harmful signals are basic physiological reactions of all living organisms
It is possible that the 30% difference between human and murine proteins is associated with sUA signalling
It has been demonstrated that Naip/Nlrc[4] inflammasome activation is sufficient to cause systemic inflammatory disease with surprising tibiotarsal joint swelling[59], the main joint affected by gout, a disease triggered by the accumulation of UA60
Summary
Host responses against harmful signals are basic physiological reactions of all living organisms. Innate immunity pattern-recognition receptors (PRRs) were first described as recognizing conserved structural components of microorganisms[1]. The discovery of Toll-like receptors[2] led scientists to understand how the immune system responds to nonself antigens in the context of an infection[3,4], in contrast with the previous model, in which the immune system reacted to all nonself antigens while being tolerant to self-antigens[5,6]. PRRs have not evolved to bind to pathogens at all; in contrast, perhaps, the pathogens evolved to attach to PRRs and enhance their own survival[7], a hypothesis that would explain a puzzling feature of PRRs: each one can attach to many different kinds of molecules. MSU activates the immune system[9,10], acts as a prooxidant molecule, stimulates chemotaxis and activates the nuclear factor-κB and MAPK pathways[11]. MSU induces the release of interleukin-1β (IL-1β) through the activation of inflammasome-dependent
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