Inflammasomes in neuroinflammatory and neurodegenerative diseases

Abstract

Neuroinflammation and neurodegeneration often result from the aberrant deposition of aggregated host proteins, including amyloid-β, α-synuclein, and prions, that can activate inflammasomes. Inflammasomes function as intracellular sensors of both microbial pathogens and foreign as well as host-derived danger signals. Upon activation, they induce an innate immune response by secreting the inflammatory cytokines interleukin (IL)-1β and IL-18, and additionally by inducing pyroptosis, a lytic cell death mode that releases additional inflammatory mediators. Microglia are the prominent innate immune cells in the brain for inflammasome activation. However, additional CNS-resident cell types including astrocytes and neurons, as well as infiltrating myeloid cells from the periphery, express and activate inflammasomes. In this review, we will discuss current understanding of the role of inflammasomes in common degenerative diseases of the brain and highlight inflammasome-targeted strategies that may potentially treat these diseases.

Keywords: disease; inflammasome; inflammation; microglia; neurodegeneration.

Figure 1. Inflammasome activation and signaling

Inflammasomes assemble in a stimulus‐specific manner. Different DAMPs and PAMPs are able to induce NLRP3, while NLRP1b responds to Bacillus anthracis lethal toxin, NLRC4 recognizes bacterial flagellin and/or the type III secretion system of bacterial pathogens, AIM2 is specifically activated by dsDNA, and pyrin recognizes the inactivation of RhoA by toxins and effector proteins. Activation of the NLRP3 inflammasome involves a two‐step mechanism. The priming signal is detected by membrane‐bound PRRs, including TLRs and C‐type lectin receptors (CLRs) and induces NF‐κB‐dependent transcription of NLRP3 and pro‐IL‐1β precursor protein, and controls post‐translational modifications that license NLRP3 activation. The second activation signal is necessary for inflammasome formation, depending on the oligomerization and subsequent activation of procaspase‐1. Active caspase‐1 then cleaves pro‐IL‐1β and pro‐IL‐18 to their mature forms IL‐1β and IL‐18 which get secreted. In addition, caspase‐1 can cleave gasdermin D, releasing its N‐terminal fragment which translocates to the plasma membrane inducing pore formation and pyroptotic cell death. In contrast to NLRP3, other inflammasome receptors do not need this initial priming signal to induce inflammasome activation and cytokine release.

Figure 2. Domain structure of inflammasomes

A subset of NLRs and ALRs can trigger the formation of inflammasomes. NLR family members have a nucleotide‐binding and oligomerization domain (NACHT/NBD), as well as leucine‐rich repeat (LRR) motifs, typically located in the center and carboxy terminus of the NLR proteins, respectively. The NACHT motif is usually flanked by an additional amino‐terminal domain, either CARD or PYD, and these domains are used for further sub‐classification of inflammasomes. These domains allow the recruitment of adaptor and effector proteins to the inflammasome signaling complex. The NLR gene family consists of 22 human members and 34 murine members, many of which the function is not always clear (Lamkanfi & Dixit, 2012; Broz & Dixit, 2016). In addition to the NLR‐containing inflammasomes, the ALR family member AIM2 can also assemble an inflammasome complex. AIM2 is characterized by an amino‐terminal PYD domain and one or two DNA‐binding HIN200 domains (Hornung et al, 2009). Pyrin, also known as TRIM20, features a PYD domain, two B‐boxes, and a coiled‐coil domain, whereas the human pyrin also has an additional C‐terminal B30.2 domain. ASC is the critical adaptor protein for many inflammasome complexes and is composed of CARD and PYD domains, the latter being necessary for homotypic interaction with a PYD‐containing inflammasome sensor (NLRP3, AIM2). Procaspase‐1 features a CARD domain, in addition to its caspase domain, and homotypic CARD interactions result in direct or indirect (via ASC) recruitment of procaspase‐1 to the inflammasome complex. Inflammasome activation involves ASC and procaspase‐1 recruitment, resulting in ASC oligomerization into a macromolecular aggregate, known as an ASC speck (Broz & Dixit, 2016).

Figure 3. Inflammasome activation in neurodegenerative disease

Inflammasomes can be activated in the CNS in response to acute injury (traumatic brain injury and stroke), autoimmune‐mediated injury (multiple sclerosis), and accumulation of misfolded or aggregated proteins in the brain (Alzheimer's disease, amyotrophic lateral sclerosis, Parkinson's disease, and prion disease). Inflammasome activation has been demonstrated in CNS‐resident cell types, including microglia, astrocytes, and neurons, but also in CNS‐infiltrating cells, such as in infiltrating macrophages. Although most research on neurodegenerative diseases has focused on the importance of the NLRP3 inflammasome, also other inflammasome types can be activated in the brain and have been demonstrated in neurodegenerative disorders. Overall, inflammasome activation results in caspase‐1‐mediated cleavage of pro‐IL‐1β and pro‐IL‐18, and the subsequent release of the mature cytokines. High levels of IL‐1β and IL‐18 can be detected in many neurodegenerative conditions and are considered to be crucial for the establishment of a chronic inflammatory environment, leading to neuronal dysfunction and eventually neurodegeneration.