NLRP3 inflammasome activation mediates radiation-induced pyroptosis in bone marrow-derived macrophages

Liu, Yangang; Chen, Ji-Kuai; Zhang, Zi-Teng; Ma, Xiaoli; Chen, Yongchun; Du, Xiu-Ming; Liu, Hong; Zong, Ying; L, Gao

doi:10.1038/cddis.2016.460

Cited by 136 publications

(108 citation statements)

References 45 publications

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“…Our evaluation found that NLRP3, one of the most widely researched members of inflammasome complexes, was the gene relevant to this process. Interestingly, Liu et al concluded the Nlrp3 inflammasome activation mediates radiation‐induced pyroptosis in primary cultured bone marrow‐derived macrophages, suggestion that targeting NLRP3 inflammasomes may serve as a potential strategy to mitigate RT‐induced damage . Of note, the addition of ALA administration to RT diminished XRT‐induced Nlrp3 inflammasome activation and the resultant secretion of IL‐1b in rectal tissues (Figure ).…”

Section: Discussionmentioning

confidence: 99%

Dual benefit of supplementary oral 5‐aminolevulinic acid to pelvic radiotherapy in a syngenic prostate cancer model

et al. 2018

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Background Normal tissue damage caused by radiotherapy remains the largest dose‐limiting factor in radiotherapy for cancer. Therefore, the aim of this study was to investigate the supplementary oral 5‐aminolevulinic acid (ALA) to standard radiation therapy as a novel radioprotective approach that would not compromise the antitumor effect of radiation in normal rectal and bladder mucosa in a syngenic prostate cancer (PCa) model. Methods To evaluate the radiosensitizing effect of ALA in vitro, clonogenic survival assays were performed in DU145, PC3, and MyC‐CaP cell lines. To evaluate the effect of ALA in vivo a single dose (25 Gy) of radiation with or without ALA was given to healthy mice. Next, a syngenic PCa model of MyC‐CaP cells in FVB mice was created, and multiple doses (12 Gy total) of radiation were administered to the mouse pelvic area with or without ALA administration. Resected tumors, recta, and urinary bladders were immunostained with antibodies against Ki‐67, γ‐H2AX, CD204, and uroplakin‐III. Total RNA levels in recta and urinary bladders were analyzed via RT2 Profiler polymerase chain reaction (PCR) arrays related to “Stress & Toxicity PathwayFinder,” “Mitochondria,” and “Inflammasomes.” Results The addition of in vitro single or in vivo repeated administration of exogenous ALA acted as a radiosensitizer for PCa cells. Rectal toxicity was characterized by histological changes including loss of surface epithelium, fibrosis, severe DNA damage, and the aggregation of M2 macrophages. Urinary bladder toxicity was characterized by bladder wall thickening and urothelium denuding. The higher dose (300 mg/kg/day) of ALA exerted a better radioprotective profile than the lower dose (30 mg/kg/day) in normal recta and urinary bladders. Out of the 252 genes tested, 35 (13.4%) were detected as relevant genes which may be involved in the radioprotective role of ALA administration. These included interleukin‐1a (IL‐1a), IL‐1b, IL‐12, chemokine (C‐X‐C motif) ligand 1 (CXCL1), CXCL3, and NLRP3. Conclusions Our study provides novel and comprehensive insights into the dual benefits including radiosensitizing PCa tumor tissues and radioprotection of normal pelvic organs from radiation therapy. Knowledge of the underlying mechanism will facilitate the search for optimal treatment parameters for supplemental oral ALA during radiotherapy for PCa.

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Section: Discussionmentioning

confidence: 99%

Dual benefit of supplementary oral 5‐aminolevulinic acid to pelvic radiotherapy in a syngenic prostate cancer model

et al. 2018

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“…hypo versus hyper fxMouse colonBarlow et al (2016) IL-1α, IL-1β, TNF-αX-ray versus γ-ray ( 137 Cs)7–25 Gy/1fxMouse brainHong et al (1995) IL-β, TNF-αγ-ray ( 137 Cs)10 Gy/1fxRat brainLee et al (2010) IL-6γ-ray ( 60 Co)10 Gy/1fxHuman alveolar carcinoma cells (A549)Gao et al (2014) IL-1β, TNF-αα-particle ( 3 He) microbeam0.5 Gy/1fxHuman lung fibroblastsZhou et al (2008) IL-6γ-ray ( 60 Co or 137 Cs)9–10 Gy/1fxMouse plasma and lungVan der Meeren et al (2003) TNF-αγ-ray ( 192 Ir)10 Gy/1fxRat brain(Kim et al 2002) IL-1α, TNF-αγ-ray ( 137 Cs)0–35 Gy/1fxMouse brainMoravan et al (2011) TNF-αX-ray2–20 Gy/1fx versus 10–40 Gy/5–20fxMouse brainGaber et al(2003) IL-1α, IL-6X-ray12 Gy/1fxMouse lung, bronchial lavage fluid, serumAo et al (2009) IL-8α-particle ( 238 Pu)0.036–0.19 Gy/1fxHuman lung fibroblastsNarayanan et al (1999) IL-1α, IL-1β, IL12p40, IL-18, TNF-α, IFN-γγ-ray ( 60 Co)5–20 Gy/1fxMurine bone marrow-derived macrophagesLiu et al (2017)Anti-inflammatory cytokines TGF-β1γ-ray ( 192 Ir)…”

Section: Radiation-induced Immune Mediatorsmentioning

confidence: 99%

Radiation, inflammation and the immune response in cancer

et al. 2018

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Radiation is an important component of cancer treatment with more than half of all patients receive radiotherapy during their cancer experience. While the impact of radiation on tumour morphology is routinely examined in the pre-clinical and clinical setting, the impact of radiation on the tumour microenvironment and more specifically the inflammatory/immune response is less well characterised. Inflammation is a key contributor to short- and long-term cancer eradication, with significant tumour and normal tissue consequences. Therefore, the role of radiation in modulating the inflammatory response is highly topical given the current wave of targeted and immuno-therapeutic treatments for cancer. This review provides a general overview of how radiation modulates the inflammatory and immune response-(i) how radiation induces the inflammatory/immune system, (ii) the cellular changes that take place, (iii) how radiation dose delivery affects the immune response, and (iv) a discussion on research directions to improve patient survival, reduce side effects, improve quality of life, and reduce financial costs in the immediate future. Harnessing the benefits of radiation on the immune response will enhance its maximal therapeutic benefit and reduce radiation-induced toxicity.

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“…b-g show the MRS of the different groups. The NAA/Cr ratio in the 15 Gy group and 25 Gy group was significantly lower than that in the control group on the 4th day after radiation injury, but the ratios at 8 weeks were partially recovered 3 h after irradiation in a dose-dependent manner [31]. These authors also showed that 10 Gy radiation in vivo induced pyroptosis and caspase-1 activation.…”

Section: Discussionmentioning

confidence: 83%

Hippocampal changes in inflammasomes, apoptosis, and MEMRI after radiation-induced brain injury in juvenile rats

et al. 2020

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Purpose: The aim of this study was to characterize changes in hippocampal inflammasomes, pyroptosis and apoptosis in juvenile rats after brain irradiation and to assess whether manganese-enhanced magnetic resonance imaging (MEMRI) reflected those changes. Materials and methods: Four-week-old male Sprague-Dawley rats received a whole-brain radiation dose of 15 Gy or 25 Gy. Hippocampal inflammasomes and apoptosis were measured using Western blot analysis at 4 days and 8 weeks after irradiation. MEMRI and magnetic resonance spectroscopy (MRS) were performed at the same time points.Results: Neither the 15 Gy nor 25 Gy group showed changes in the expression of inflammasome proteins absent in melanoma 2 (AIM2), gasdermin-D (GSDMD), nucleotide oligomerization domain-like receptor protein 1 (NLRP1) and NLRP3 at 4 days or 8 weeks after radiation injury (P > 0.05). Furthermore, the expression levels of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18 were not significantly different among the groups (P > 0.05). The expression levels of cleaved caspase-1 and -3, indicators of apoptosis, were higher in the irradiation groups than in the control group at 4 days post irradiation, especially for caspase-3 (P < 0.05), but this increase was slightly attenuated at 8 weeks after radiation injury. Four days post irradiation, the MEMRI signal intensity (SI) in the irradiation groups, especially the 25 Gy group, was significantly lower than that in the control group (P < 0.05). Eight weeks after radiation injury, the SI of the 15 Gy group and the 25 Gy group recovered by different degrees, but the SI of the 25 Gy group was still significantly lower than that of the control group (P < 0.05). On day 4 post irradiation, the metabolic ratio of N-acetylaspartate (NAA) to creatine (Cr) in the 15 Gy group and 25 Gy group was significantly lower than that in the control group (P < 0.05). The NAA/Cr ratio in the 15 Gy group recovered to control levels at 8 weeks (P > 0.05), but the NAA/Cr ratio in the 25 Gy group remained significantly lower than that in the control group (P < 0.05).Conclusion: Radiation-induced brain injury is dose-dependently associated with apoptosis but not inflammasomes or pyroptosis, and the change in apoptosis can be detected by MEMRI.

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NLRP3 inflammasome activation mediates radiation-induced pyroptosis in bone marrow-derived macrophages

Cited by 136 publications

References 45 publications

Dual benefit of supplementary oral 5‐aminolevulinic acid to pelvic radiotherapy in a syngenic prostate cancer model

Dual benefit of supplementary oral 5‐aminolevulinic acid to pelvic radiotherapy in a syngenic prostate cancer model

Radiation, inflammation and the immune response in cancer

Hippocampal changes in inflammasomes, apoptosis, and MEMRI after radiation-induced brain injury in juvenile rats

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