Table 1.
In vivo studies involving radiation-induced NLRP3 inflammasome activation.
| Animal | Radiation dose | Irradiated tissue | Observation period | NLRP3 activation-wise results | Possible connections | Reference |
|---|---|---|---|---|---|---|
| Male Wistar rats | 7.5 Gy/day for five consecutive days | mouth | 14 days | 1. Increase in the NLRP3 and ASC protein levels and mRNA expression in irradiated tongues 2. Expression of pro-caspase-1 mRNA increased with irradiation followed by decreased protein levels 3. Increase in NF-κB mRNA and protein levels in the cytosol and nuclei of irradiated rat tongues |
1. Increased mitochondrial LPO levels, mRNA, and protein levels of GPx, GSSG/GSH ratio, decreased GRd expression 2. Increased iNOS and i-mtNOS expression 3. Reduction in the expression of respiratory complexes I, III, and IV and the ATPase as well as a reduction in mitochondrial mass 4. Increase in autophagy/mitophagy markers Atg12, Beclin-1, and Nix in irradiated tongues |
(41) |
| C57BL/6 mice (6 to 8 weeks old) | 2, 4, 16 Gy | Lung | 1, 4, 8 weeks | 1. NLRP3 inflammasome was activated in mouse lungs by irradiation starting from 2 Gy, the extent of expression was not correlated with radiation dose 2. NLRP3 activation was continued for 8 weeks until sacrifice |
1. NLRP3 activation was mainly found in the airway, rather than in the lung parenchyma | (40) |
| Human biopsy | Irradiated human artery | 156 weeks (median) post-radiation therapy | 1. Apoptosis and NLR signaling pathways are the most differentially expressed in irradiated human arteries 2. Marked elevation of genes encoding IL-1α and IL-1β, caspase-1 and NLRP3 |
1. Irradiated arterial biopsies had a marked increase in pro-caspase-1 and caspase-1 | (30) | |
| male Wistar rats (3-month-old) | 7.5 Gy/day for five consecutive days | mouth | 14 days | 1. Increased protein level of NF-κB subunit p65 in the nucleus and cytosol, with increased expression of IL-1β, TNFα, and COX-2 2. Increased NLRP3 protein level in intestine, followed by decreased pro-caspase-1 and increased IL-1β |
1. Increased ROS and NO levels in intestine tissue 2. Intestine show reduced expressions of respiratory complexes I, II, III and ATP synthase 3. decreased activity of antioxidant: GPx, GRd, Mn-SOD, with increased GSSG/GSH ratio |
(8) |
| Adult female BALB/c mice | 10 Gy | abdomen | 6-15 days | 1. On day 6, NLRP3, caspase-1, IL-1β and IL-18 mRNA levels were elevated in Intestinal cell, accompanied by increased caspase1 activity 2. IL-1, IL-8, MCP-1, TNF-α mRNA levels were elevated |
1. Increased apoptosis and DNA damage (measured by γ-H2AX expression) were detected 2. IR increases SOD activity and concentration of GPx, GR and increases GSSG/GSH ratio in Intestinal cells on day 6 |
(47) |
| WT C57BL/6J male mice | 9.5 Gy | Whole-body radiation | 3 hours and 30 days | 1. Cleaved-caspase-1 (p10) and IL-1β protein levels were induced in spleen cells 3 hours after irradiation, with a mild increase in NLRP3 protein level 2. Staining for cleaved-caspase-1 in spleen marginal zone cells were elevated 3 hours after radiation 3. Nlrp3 knockout was associated with significantly improved survival at 30 days after irradiation |
1. Cleaved-caspase-1 were hardly observed in the white pulp cells of the spleen (rich in lymphocytes) | (48) |
| Male 5–7-week-old CD-1 mice, Male (caspase1 -/-) mice, Male 7-week-old C57BL/6J mice |
0.5, 1, 2, 4 Gy | Whole-body radiation | 1, 2, 4, 6 hours or 1, 3, 7, and 14 days | 1. A dose-dependent increase in cleaved-caspase-1(p10) levels were examined in spleen cells 1 day after radiation but was not detectable at 1 or 4 hours after radiation 2. 2 Gy radiation induced increases of cleaved-caspase-1 sustained for 7 days and returned to baseline levels on day 14 3. PI-Annexin V double positive spleen cells were increased 4 hours after 2 Gy radiation, reached highest level on day 1 and returned to baseline on day 14 4. Caspase-1 deficient mice show increased surviving spleen cells 1 day after 2 Gy radiation, as well as lower proportion of PI-Annexin V double positive cells |
1. plasma uric acid levels were increased at 2, 6 hours, and 1 day after radiation exposure 2. Blocking uric acid generation before and after 2 Gy radiation resulted in the decreased inflammasome activation |
(44) |
| C57BL/6 female mice (8 weeks old) | 75 Gy | Left lung | 2 and 3 weeks | 1. The expression of NLRP3 inflammasome-related genes (Nlrp3, Il1a, Il-1b, and Casp1) in lung tissue were increased 3 weeks after radiation | (46) | |
| C57BL/6 female mice (6 weeks old) | 75 Gy | Left lung | 21 days | Increased mRNA levels of inflammasome related genes (Nlrp1, Nlrp3, Il-1b, and Casp1) in irradiated lung tissue | (49) | |
| Male C57/6 mice | 7.2 Gy, delivered in 5 days | total body irradiation | 14 days | 1. IR increased mRNA and protein levels of IL-1β and NLRP3 in thymus and spleen 2. Strong increases of IL-1β protein levels in intestine tissue as well as serum |
(50) | |
| C57BL/6 mice, NLRP3 macrophage-specific knockout mice |
14 or 16 Gy | Whole-body radiation | 7 days | 1. 16 Gy radiation: all NLRP3-deficient mice died on day 6, 20% of WT mice survived until day 15 2. 14 Gy radiation: on day 15, 75% WT mice and 50% NLRP3-deficient mice survived |
1. Higher level of ROS generation in the colon of NLRP3-deficient mice than in that of WT mice 2. NLRP3-deficient mice had a lower expression of barrier protein (ZO-1, E-cadherin, calaudin-2) than WT 3. cGAS-STING activation: elevated IFN-β levels in serum of NLRP3-deficient mice compared to WT. With increased p-TBK-1 and p-IRF3 protein levels in colon tissue |
(51) |
| 3-month-old C57BL/6 mice | 40 Gy | The left thigh skin | 8 weeks | 1. mRNA and protein levels of NLRP3, caspase-1, and IL-1β were significantly increased in irradiated skin tissue | 1. Increased serum 8-OHdG levels and skin γH2AX expression levels were detected 4 weeks after radiation 2. radiation causes increase in serum ROS levels as well as 4-HNE and 3-NT in skin tissue |
(42) |
ROS, reactive oxygen species; LPO, lipid peroxidation; GPx, glutathione peroxidase; GSSG, glutathione disulfide; GSH, glutathione; GR, glutathione Reductase; iNOS, inducible nitric oxide synthase; i-mtNOS, mitochondrial iNOS; BALF, bronchoalveolar lavage fluid; MDA, malondialdehyde; SOD, superoxide dismutase; Mn-SOD, manganese-dependent superoxide dismutase; PI, propidium iodide; p-TBK-1, phosphorylated TANK binding kinase 1; p-IRF3, phosphorylated interferon regulatory factor 3; 8-OhdG, 8-hydroxy-2’-deoxyguanosine; 4-HNE, 4-hydroxynonenal; 3-NT, 3-Nitrotyrosine.