From inflammatory signaling to neuronal damage: Exploring NLR inflammasomes in ageing neurological disorders

Abstract

The persistence of neuronal degeneration and damage is a major obstacle in ageing medicine. Nucleotide-binding oligomerization domain (NOD)-like receptors detect environmental stressors and trigger the maturation and secretion of pro-inflammatory cytokines that can cause neuronal damage and accelerate cell death. NLR (NOD-like receptors) inflammasomes are protein complexes that contain NOD-like receptors. Studying the role of NLR inflammasomes in ageing-related neurological disorders can provide valuable insights into the mechanisms of neurodegeneration. This includes investigating their activation of inflammasomes, transcription, and capacity to promote or inhibit inflammatory signaling, as well as exploring strategies to regulate NLR inflammasomes levels. This review summarizes the use of NLR inflammasomes in guiding neuronal degeneration and injury during the ageing process, covering several neurological disorders such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, and peripheral neuropathies. To improve the quality of life and slow the progression of neurological damage, NLR-based treatment strategies, including inhibitor-related therapies and physical therapy, are presented. Additionally, important connections between age-related neurological disorders and NLR inflammasomes are highlighted to guide future research and facilitate the development of new treatment options.

Keywords: Ageing; NLR inflammasomes; Neurological disorders; Treatment.

Fig. 1

A model of cell signaling and its activation using NLRP1 and NLRP3 as examples. The ASC, PYD and CARD, are recruited by NLRP3 upon activation by a risk-associated molecular pattern to form helical fibers. Pro-caspase-1 is then recruited and activated to generate mature caspase-1. Pro-IL-1β and pro-IL-18 are then converted by caspase-1 to mature forms of IL-1β and IL-18; NLRP1 has an N-terminal PYD, a structural domain and LRR. Unlike other NLRPs, NLRP1 has a C-terminal extension containing a FIIND and a CARD. Thus, the steps in NLRP1 inflammasome activation of IL-1β and IL-18 are roughly as follows: the PYD or CARD that activates the PRR is bridged to the CARD of pro-caspase-1. Next, pro-CASP1 undergoes near-sensing autoprotein hydrolysis to produce an active enzyme (CASP1) that cleaves and activates inflammatory cytokines (i.e., IL-1β and IL-18). ASC, apoptosis-associated speckle-like protein; PYD, pyrin domain; NACHT, nucleotide-binding oligomerization domain; NF-κB, nuclear factor kappa B; CARD, caspase activation and recruitment domain; LRR, leucine-rich repeat; FIIND, function-to-investigation domain; CASP1, caspase-1; IL, interleukin; NLRP, nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing; NLRC, nucleotide-binding oligomerization domain, leucine-rich repeat and caspase recruitment domain-containing.

Fig. 2

The pattern of NLR inflammasomes involvement in the activation of pro-inflammatory cytokines. NLR inflammasomes are linked with several diseases related to neurodegeneration and nerve damage such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, stroke, and peripheral neuropathy. Certain NLR inflammasomes including NLRP1/2/3/10 and NLRC4 can trigger the conversion of pro-IL-1β or pro-IL-18 to mature forms of pro-inflammatory cytokine IL-1β or IL-18. In contrast, NLRP10, NLRP6 and NLRC5 exhibit inhibitory effects on the above processes. Aβ, Amyloid β; α-syn, α-synuclein; ROS, reactive oxygen species; mtDNA, mitochondrial DNA; SOD1, superoxide dismutase 1; TDP-43, transactive response DNA-binding protein-43; VCP, valosin-containing protein; TXNIP, thioredoxin-interacting protein; ICH: intracerebral hemorrhage; I/R, ischemia-reperfusion; Nrf2: Nuclear factor erythroid 2-related factor 2; HO-1, heme oxygenase-1; CASP1, caspase-1; IL, interleukin; NLRP, nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing; NLRC, nucleotide-binding oligomerization domain, leucine-rich repeat and caspase recruitment domain-containing.

Fig. 3

A) Cellular patterns of NLR inflammasomes in Alzheimer's disease and Parkinson's disease. α-syn can induce IL-1β synthesis through interaction with Toll-like receptor 2 (TLR2) and inflammasomes; endocytosis of α-syn, which increases ROS accumulation by inhibiting AMPK phosphorylation, induces lysosomal swelling and damage, increases lysosomal protease expression in the cytoplasm, and ultimately activates NLRP3; mitochondrial dysfunction may increase NLRP3 inflammasome activity, and NLRP3 causes mitochondrial damage, promotes the release of mtDNA in the cytoplasm, as well as promotes the production of mitochondrial reactive oxygen species; Aβ triggers the formation of TLR4 heterodimers, which in turn leads to the activation of the transcription factor NF-κB, thus promoting NLRP3 activation and pro-IL-1β transcription; P2X7R is activated by signals released from dying neurons, inducing K+ efflux and Ca2+ influx, promoting NLRP3 activation; NLRC4 is activated in AD and releases IL-1β; NLRP1 can reactivate caspase-6, and tau is further catabolized by caspase-6, thus further inducing negative neurological effects of Aβ; NLRP10 inhibits caspase 1 activation and IL-1β release, negatively regulating the disease. B) Cellular patterns of NLR inflammasomes in amyotrophic lateral sclerosis. SOD1 exhibits neurotoxic effects in motor neuron-microglia cultures, where it interacts with CD14 and activates NLRP3, caspase-1, as evidenced by increased production of pro-inflammatory cytokines (including IL-1β and IL-18) and the transcription factor NF-κB; in brain tissue from mutant SOD1 rats, NLRC4 and caspase- 1 activation was shown to be expressed; chronic inflammation caused by NF-κβ signaling stimulation mediates TDP-43 proteinopathy, and TDP-43 activates NLRP3 inflammasomes, leading to increased IL-1β production; VCP mutations are an etiology of ALS and are associated with NLRP3 inflammasome activation. C) Cellular patterns of NLR inflammasomes in Stroke. In I/R, NLRP1/3/10 exacerbate the symptoms of cerebral ischemia by activating the release of IL-1β and IL-18; in I/R, NLRC5 reduces the expression of Bcl2-associated X protein (Bax) and ROS through the Nrf2/HO-1 pathway, as well as NLRC5 reduces inflammation, oxidative damage, and ameliorates cerebral ischemia by preventing the activation of the NF-κB pathway; in ICH, NLRP6 inflammasome inhibits inflammatory signaling by negatively regulating the NF-κB activation pathway. D) Cellular patterns of NLR inflammasomes in Peripheral neuropathy. In diabetes mellitus, the TRX system and TXNIP interact, and when ROS produced by cells during hyperglycemia cause TXNIP to separate from TRX, enabling it to attach to NLRP3, which activates the NLRP3 inflammasome in Schwann cells, causing them to release IL-1β and induce neuroinflammatory injury to Schwann cells; in RA, the inflammatory response in the synovial fluid leads to peripheral nerve injury, and the release of damaged nerve ATP and PG activate P2X4R. Subsequently, high Ca2+ influx into macrophages may activate p38 MAPK, leading to the release of BDNF and PGE2 into synovial fluid and peripheral nerves as well as activating the NLRP1 inflammasome; in RA, Ca2+ influx stimulates P2X7R, inducing the production of pro-inflammatory factors and stimulating the NLRP1 inflammasome. TLR, toll-like receptor; α-syn, α-synuclein; IL, interleukin; AMPK, adenosine monophosphate-activated protein kinase; ROS, reactive oxygen species; NF-κB, nuclear factor kappa B; SOD1, superoxide dismutase 1; TDP-43, transactive response DNA-binding protein-43; VCP, valosin-containing protein; ICH: intracerebral hemorrhage; Nrf2: Nuclear factor erythroid 2-related factor 2; HO-1, heme oxygenase-1; TXNIP, thioredoxin-interacting protein; Bax, Bcl2-associated X protein; TRX, thioredoxin; PG, prostaglandins; p38 MAPK, p38 mitogen-activated protein kinase; BDNF, brain-derived neurotrophic factor; PGE2, prostaglandin E2; NLRP, nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain-containing; NLRC, nucleotide-binding oligomerization domain, leucine-rich repeat and caspase recruitment domain-containing.