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I. Tsuboi et al.
mice were treated repeatedly with LPS, the numbers of white blood cells and platelets decreased rapidly after each treatment, followed by a prompt return to near or above pretreatment levels; the number of red blood cells remained unchanged.22 Thus, the changes in the number of peripheral blood cells in SAMR1 mice after repeated LPS treatment were comparable with those in BALB/c mice after repeated LPS treatment.
The number of preB-cell progenitor cells in bone mar- row was significantly decreased in SAMP1/TA-1 mice after LPS treatment, whereas the number of myeloid pro- genitor cells remained unchanged (Figure 6A,B). These results may indicate that the number of peripheral lym- phocytes was more significantly decreased in SAMP1/TA- 1 mice than in SAMR1 mice (Figure 1A). The number of erythroid progenitor cells was more significantly decreased in LPS-treated SAMP1/TA-1 mice than in LPS- treated SAMR1 mice (Figure 6C). Furthermore, the num- ber of megakaryocyte progenitor cells in LPS-treated SAMP1/TA-1 mice was decreased, whereas the number of megakaryocyte progenitor cells in LPS-treated SAMR1 mice was increased (Figure 6D). These results suggest that severe anemia and thrombocytopenia in LPS-treated SAMP1/TA-1 mice may be in part due to profound and prolonged suppression of erythropoiesis and throm- bopoiesis in the bone marrow. Taken together, the pro- longed and tremendous cytokine storm induced by LPS may have disrupted the dynamics of hematopoiesis.
When repeatedly treated with LPS, ferric iron storage in the spleen of SAMP1/TA-1 mice was markedly decreased
compared with that of non-treated SAMP1/TA-1 mice (Figure 4C vs. 4D). A similar phenomenon was observed in Typhimurium-infected mice, a model of sHLH, which showed increased erythropoiesis in the spleen.25 When C57BL/6 mice are treated with an inflammatory com- pound, erythropoiesis in the spleen is accelerated, where- as erythropoiesis in the bone marrow is suppressed.42,43 Taken together, splenic erythropoiesis in LPS-treated SAMP1/TA-1 mice may be accelerated to compensate for suppression of erythropoiesis, resulting in decreased fer- ric-iron storage in the spleen.
In this study, we demonstrated that SAMP1/TA-1 mice treated repeatedly with LPS develop an sHLH-like dis- ease. SAMP1/TA-1 mice are susceptible to infection due to latent deterioration of immunological function. Bacterial infections are reported in 9% of adult cases of HLH.44,45 LPS is a characteristic component of the wall of Gram-negative bacteria. Several cases of adult-onset sHLH associated with severe Gram-negative bacterial infection such as Salmonella typhi, Escherichia coli, Klebsiella pneumoniae and Haemophils parainfluenzae have been reported.46-49 Thus, SAMP1/TA-1 mice are a useful model to investigate the pathogenesis of bacterial infec- tion-associated sHLH.
Acknowledgments
The authors would like to thank Sonoko Araki and Miyuki Yuda for technical assistance. This work was supported in part by a Grant-in Aid for Scientific Research C from the Japan Society for the Promotion of Science, grant number JP18K06846.
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