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A critical role of toll-like receptor 4 (TLR4) and its' in vivo ligands in basal radio-resistance.

Liu C, Zhang C, Mitchel RE, Cui J, Lin J, Yang Y, Liu X, Cai J - Cell Death Dis (2013)

Bottom Line: We found that exposure to radiation leads to significant endotoxemia that also confers endogenous protection from irradiation.Our data suggest, it is important not to give antibiotics that may sterilize the gut before the whole body irradiation.Further, these data also suggest that management of gut flora through antibiotic or possibly probiotic therapy may alter the innate response to the total body irradiation.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai, People's Republic of China.

ABSTRACT
Toll-like receptor-4 (TLR4) plays a critical role in innate and acquired immunity, but its role in radio-resistance is unknown. We used TLR4 knockout (KO,(-/-)) mice and gut commensal depletion methods, to test the influence of TLR4 and its' in vivo agonist on basal radio-resistance. We found that mice deficient in TLR4 were more susceptible to IR-induced mortality and morbidity. Mortality of TLR4-deficient mice after IR was associated with a severe and persistent bone marrow cell loss. Injection of lipopolysaccharide into normal mice, which is known to activate TLR4 in vivo, induced radio-resistance. Moreover, TLR4 in vivo ligands are required for basal radio-resistance. We found that exposure to radiation leads to significant endotoxemia that also confers endogenous protection from irradiation. The circulating endotoxins appear to originate from the gut, as sterilization of the gut with antibiotics lead to increased mortality from radiation. Further data indicated that Myd88, but not TRIF, may be the critical adaptor in TLR4-induced radio-resistance. Taken together, these data strongly suggest that TLR4 plays a critical role in basal radio-resistance. Our data suggest, it is important not to give antibiotics that may sterilize the gut before the whole body irradiation. Further, these data also suggest that management of gut flora through antibiotic or possibly probiotic therapy may alter the innate response to the total body irradiation.

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Increased mortality of TLR4−/− mice after IR associated with a severe and persistent BMC loss. (a) TLR4+/− mice and TLR4−/− mice were irradiated with 5 Gy and the femur was collected and subjected to an H and E assay at days 0, 1, 5, 14 and 28 post-IR. All images are × 100. The figure shows a typical H and E image of three independent experiments (N=3). (b, c). Kinetics of the BMC number and PBMC number in TLR4+/− mice and TLR4−/− mice after 5 Gy. (b) The BMC number was counted at days 0, 1, 5, 14 and 28 post-IR. (c) The PBMC numbers were measured at days 0, 1, 5, 14, 20 and 28 post-IR. *P<0.05
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fig2: Increased mortality of TLR4−/− mice after IR associated with a severe and persistent BMC loss. (a) TLR4+/− mice and TLR4−/− mice were irradiated with 5 Gy and the femur was collected and subjected to an H and E assay at days 0, 1, 5, 14 and 28 post-IR. All images are × 100. The figure shows a typical H and E image of three independent experiments (N=3). (b, c). Kinetics of the BMC number and PBMC number in TLR4+/− mice and TLR4−/− mice after 5 Gy. (b) The BMC number was counted at days 0, 1, 5, 14 and 28 post-IR. (c) The PBMC numbers were measured at days 0, 1, 5, 14, 20 and 28 post-IR. *P<0.05

Mentions: To further analyze the reason for increased mortality of TLR4−/− mice after IR, mass biopsy assays were performed for a histological study of the radiation-induced tissue damage in TLR4+/− and TLR4−/− mice. A 5 Gy total body irradiation (TBI) was shown to induce tissue damage in multiple organs of both TLR4+/− mice and TLR4−/− mice, but TLR4−/− mice showed greater injury in bone marrow (BM), colon, kidney, spleen, testis and lung as detected by hematoxylin and eosin (H and E) assays (Figure 2a and Supplementary Figure S4). The histological study results also indicated that the main cause of death in TLR4−/− mice may be severe and persistent BMC loss. As shown in Figure 2a, 5 Gy exposure injured BM and decreased the BMC number from TLR4+/− mice. However, the BM showed the greatest damage and cell loss at day 5 post-IR and all mice demonstrated significant BM tissue repair at day 14 post-IR, while by day 28, BM from TLR4+/− mice was well repaired. However, in the TLR4−/− mice, BMC loss were more severe and more persistent. The TLR4−/− BMCs showed only slightly greater damage than TLR4+/− BMCs at day 1 and day 5, but the greatest damage and cell loss occurred at day 14, and was much more severe than day 14 in TLR4+/− BM (P<0.05). The TLR4−/− mice that survived demonstrated only partial BM tissue repair at day 28 post-IR. These data are consistent with the death of nearly half the TLR4−/− mice 9–17 days after 5 Gy (Figure 1b). The BMC and peripheral blood mononuclear cell (PBMC) numbers in TLR4+/− and TLR4−/− mice were also counted on different days after 5 Gy exposure. The PBMC numbers of both genotypes of mice were decreased after irradiation. However, TLR4−/− mice showed much more PBMC and BMC destruction (Figures 2b and c). These data consistently indicate that the main cause of death in TLR4−/− mice may be a severe and persistent BMC loss after IR, especially after a dose of 5 Gy.


A critical role of toll-like receptor 4 (TLR4) and its' in vivo ligands in basal radio-resistance.

Liu C, Zhang C, Mitchel RE, Cui J, Lin J, Yang Y, Liu X, Cai J - Cell Death Dis (2013)

Increased mortality of TLR4−/− mice after IR associated with a severe and persistent BMC loss. (a) TLR4+/− mice and TLR4−/− mice were irradiated with 5 Gy and the femur was collected and subjected to an H and E assay at days 0, 1, 5, 14 and 28 post-IR. All images are × 100. The figure shows a typical H and E image of three independent experiments (N=3). (b, c). Kinetics of the BMC number and PBMC number in TLR4+/− mice and TLR4−/− mice after 5 Gy. (b) The BMC number was counted at days 0, 1, 5, 14 and 28 post-IR. (c) The PBMC numbers were measured at days 0, 1, 5, 14, 20 and 28 post-IR. *P<0.05
© Copyright Policy - open-access
Related In: Results  -  Collection

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fig2: Increased mortality of TLR4−/− mice after IR associated with a severe and persistent BMC loss. (a) TLR4+/− mice and TLR4−/− mice were irradiated with 5 Gy and the femur was collected and subjected to an H and E assay at days 0, 1, 5, 14 and 28 post-IR. All images are × 100. The figure shows a typical H and E image of three independent experiments (N=3). (b, c). Kinetics of the BMC number and PBMC number in TLR4+/− mice and TLR4−/− mice after 5 Gy. (b) The BMC number was counted at days 0, 1, 5, 14 and 28 post-IR. (c) The PBMC numbers were measured at days 0, 1, 5, 14, 20 and 28 post-IR. *P<0.05
Mentions: To further analyze the reason for increased mortality of TLR4−/− mice after IR, mass biopsy assays were performed for a histological study of the radiation-induced tissue damage in TLR4+/− and TLR4−/− mice. A 5 Gy total body irradiation (TBI) was shown to induce tissue damage in multiple organs of both TLR4+/− mice and TLR4−/− mice, but TLR4−/− mice showed greater injury in bone marrow (BM), colon, kidney, spleen, testis and lung as detected by hematoxylin and eosin (H and E) assays (Figure 2a and Supplementary Figure S4). The histological study results also indicated that the main cause of death in TLR4−/− mice may be severe and persistent BMC loss. As shown in Figure 2a, 5 Gy exposure injured BM and decreased the BMC number from TLR4+/− mice. However, the BM showed the greatest damage and cell loss at day 5 post-IR and all mice demonstrated significant BM tissue repair at day 14 post-IR, while by day 28, BM from TLR4+/− mice was well repaired. However, in the TLR4−/− mice, BMC loss were more severe and more persistent. The TLR4−/− BMCs showed only slightly greater damage than TLR4+/− BMCs at day 1 and day 5, but the greatest damage and cell loss occurred at day 14, and was much more severe than day 14 in TLR4+/− BM (P<0.05). The TLR4−/− mice that survived demonstrated only partial BM tissue repair at day 28 post-IR. These data are consistent with the death of nearly half the TLR4−/− mice 9–17 days after 5 Gy (Figure 1b). The BMC and peripheral blood mononuclear cell (PBMC) numbers in TLR4+/− and TLR4−/− mice were also counted on different days after 5 Gy exposure. The PBMC numbers of both genotypes of mice were decreased after irradiation. However, TLR4−/− mice showed much more PBMC and BMC destruction (Figures 2b and c). These data consistently indicate that the main cause of death in TLR4−/− mice may be a severe and persistent BMC loss after IR, especially after a dose of 5 Gy.

Bottom Line: We found that exposure to radiation leads to significant endotoxemia that also confers endogenous protection from irradiation.Our data suggest, it is important not to give antibiotics that may sterilize the gut before the whole body irradiation.Further, these data also suggest that management of gut flora through antibiotic or possibly probiotic therapy may alter the innate response to the total body irradiation.

View Article: PubMed Central - PubMed

Affiliation: Department of Radiation Medicine, Faculty of Naval Medicine, Second Military Medical University, Shanghai, People's Republic of China.

ABSTRACT
Toll-like receptor-4 (TLR4) plays a critical role in innate and acquired immunity, but its role in radio-resistance is unknown. We used TLR4 knockout (KO,(-/-)) mice and gut commensal depletion methods, to test the influence of TLR4 and its' in vivo agonist on basal radio-resistance. We found that mice deficient in TLR4 were more susceptible to IR-induced mortality and morbidity. Mortality of TLR4-deficient mice after IR was associated with a severe and persistent bone marrow cell loss. Injection of lipopolysaccharide into normal mice, which is known to activate TLR4 in vivo, induced radio-resistance. Moreover, TLR4 in vivo ligands are required for basal radio-resistance. We found that exposure to radiation leads to significant endotoxemia that also confers endogenous protection from irradiation. The circulating endotoxins appear to originate from the gut, as sterilization of the gut with antibiotics lead to increased mortality from radiation. Further data indicated that Myd88, but not TRIF, may be the critical adaptor in TLR4-induced radio-resistance. Taken together, these data strongly suggest that TLR4 plays a critical role in basal radio-resistance. Our data suggest, it is important not to give antibiotics that may sterilize the gut before the whole body irradiation. Further, these data also suggest that management of gut flora through antibiotic or possibly probiotic therapy may alter the innate response to the total body irradiation.

Show MeSH
Related in: MedlinePlus