Deregulated inflammasome signaling in disease

Abstract

Inflammasomes are multi-protein complexes that sense microbial molecules and endogenous danger signals in intracellular compartments. Inflammasome assembly results in caspase-1 activation, which in turn drives maturation and secretion of the pro-inflammatory cytokines interleukin 1β (IL-1β) and IL-18, and induces pyroptosis to eliminate the infectious agent. The importance of inflammasomes in regulating immune responses was recognized with the discovery of polymorphisms in genes encoding inflammasome components and their linkage to aberrant production of IL-1β and IL-18 in autoimmune and hereditary periodic fevers syndromes. We review the current knowledge on the role of inflammasomes in regulating innate and adaptive immune responses with an emphasis on the role of these immune complexes in autoinflammatory disorders and autoimmune diseases such as colitis, type I diabetes, multiple sclerosis and vitiligo.

Fig. 1. Composition of inflammasome complexes

The murine NOD-like receptor (NLR) proteins NLRP1b, NLRC4 and NLRP3, and the HIN-200 protein AIM2 assemble inflammasomes in a stimulus-specific manner. NLRP1b recognizes the cytosolic presence of the Bacillus anthracis lethal toxin. The NLRC4 inflammasome is assembled after detection of bacterial flagellin or the basal body rod component of the bacterial type III and type IV secretion systems. NLRP3 is activated when macrophages are exposed to UV irradiation, microbial PAMPs, endogenous DAMPs such as ATP, or crystals such as monosodium urate, silica, and asbestos. AIM2 directly binds dsDNA in the cytosol to induce caspase 1 activation in cells infected with Francisella tularensis, Listeria monocytogenes, or DNA viruses such as cytomegalovirus and vaccinia virus. The bipartite adapter protein ASC is required for assembly of the NLRP3 and AIM2 inflammasomes, whereas the Nlrp1b and Nlrc4 inflammasomes exist in variants that either contain or lack ASC.

Fig. 2. Mechanisms of therapeutic molecules interfering with inflammasome effector pathways

Anakinra (Kineret, Amgen) corresponds to a recombinant form of the IL-1 receptor and thus targets the IL-1 receptor to displace endogenous IL-1 from the receptor. In contrast, canakinumab (Ilaris, Novartis) is a human IL-1β neutralizing monoclonal antibody raised against human IL-1β, whereas rilonacept (Arcalyst, Regeneron) represents the ligand-binding domains of human IL-1 receptor (IL-1R1) and IL-1 receptor accessory protein (IL-1RAcP) that are fused with the F_c portion of a human immunoglobulin G1 (IgG1). The latter two molecules target IL-1β in circulation, thus scavenging it from the IL-1 receptor. Finally, VX-765 (Vertex Pharmaceuticals) is a small-molecule inhibitor that specifically inhibits caspase-1 in activated immune cells.

Fig. 3. NLR- and TLR-mediated regulation of cytokine production and autophagosome formation

Members of the Toll-like receptor (TLR) and NOD-like receptor (NLR) families recognize conserved microbial components called pathogen-associated molecular patterns (PAMPs) that correspond with molecules vital for microbial survival such as flagellin, nucleic acid structures unique to bacteria and viruses and bacterial cell wall components such as lipopolysaccharide (LPS). TLRs are located at the cell surface and in endosomes of immune cells, whereas NOD-like receptors (NLRs) and HIN-200 proteins detect pathogens located in intracellular compartments. PAMP recognition by these receptors triggers a number of protective responses, including the production of pro-inflammatory cytokines and chemokines through activation of the transcription factors NF-κB and AP-1. In addition, the NLR proteins Nod1 and Nod2 may regulate antigen presentation and bacterial clearance by promoting autophagosome formation through the recruitment of Atg16L1 to the plasma membrane. Finally, the NLRs Nlrp1b, Nlrp3 and Nlrc4; and the HIN-200 protein AIM2 induce assembly of inflammasome complexes, which are responsible for caspase-1 activation and the subsequent secretion of mature IL-1β and IL-18.