Immunology in clinic review series; focus on autoinflammatory diseases: role of inflammasomes in autoinflammatory syndromes

Abstract

OTHER THEMES PUBLISHED IN THIS IMMUNOLOGY IN THE CLINIC REVIEW SERIES Allergy, Host Responses, Cancer, Type 1 diabetes and viruses, Metabolic diseases.

Summary: Autoinflammatory syndromes are disorders characterized by the hyperactivation of the innate immune system in the absence of microbial infection or autoantibody production. Some autoinflammatory syndromes are associated with recurrent episodes of fever and systemic inflammation that are caused by dysregulated activation of inflammasomes, molecular platforms responsible for the activation of caspase-1 and the production of interleukin (IL)-1β. In this review we will discuss the role of IL-1β and the inflammasomes in host defence and how mutations of two genes, NLRP3 and PYRIN, leads to the autoinflammatory syndromes, cryopyrin-associated periodic syndromes (CAPS) and familial Mediterranean fever (FMF). Both CAPS and FMF are characterized by increased inflammasome activity and overproduction of IL-1β which is ultimately responsible for disease manifestations. Importantly, understanding the molecular mechanisms of these syndromes has led to effective treatment for these rare diseases with biological drugs that target IL-1β-mediated signalling.

Fig. 1

Right: nucleotide-binding domain and leucine-rich repeat containing family pyrin domain containing 3 (NLRP3) forms an inflammasome only in the presence of activating signals. Left: disease-associated mutations in NLRP3 are gain-of-function mutation located in the nucleotide oligomerization domain (NOD) domain that lead to a constitutive active protein. Cytosolic K⁺ inhibits the formation of the NLRP3-inflammasome, but fails to do so in the presence of NLRP3 gain-of-function mutations.

Fig. 2

Two different models have been proposed to explain how mutations in PYRIN lead to familial Mediterranean fever (FMF). In one model pyrin is a positive regulator and promote the activation of caspase-1 in response to specific stimuli. Dominant gain-of-function mutations lead to a constitutive active protein, similarly to what happen for the gain-of-function mutation in nucleotide-binding domain and leucine-rich repeat containing family pyrin domain containing 3 (NLRP3). Alternatively, pyrin is a negative regulator of caspase-1. According to this model, recessive loss-of-function mutations fail to control the activation of caspase-1 leading to the inflammatory response observed in FMF.