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I. Tsuboi et al.
topenia, hypofibrinogenemia, hyperferritinemia, and hemophagocytosis in peripheral blood, the bone marrow, and the spleen. These features are compatible with sHLH.
sHLH is a severe and potentially fatal condition that leads to overwhelming inflammation. Central to its patho- genesis is a cytokine storm with markedly increased levels of numerous proinflammatory cytokines such as IL-1β, IL- 6, TNF-α, and IFN-g. The levels of gene expression of IL- 1β, IL-6, TNF-α, and IFN-g were all markedly upregulated in the liver and spleen during the first 6 h after the first LPS treatment in both SAMR1 and SAMP1/TA-1 mice (Figure 7). However, the subsequent time course of gene expres- sion for the cytokines in the liver and spleen were differ- ent between SAMR1 and SAMP1/TA-1 mice. Namely, the upregulation of IL-1β, IL-6, TNF-α, and IFN-g in the liver of SAMP1/TA-1 mice was prolonged compared with that in SAMR1 mice (Figure 7A). These data suggest that pro-
A
B
Figure 7. Changes in the levels of gene expression of cytokines and chemokines in the liver and spleen in SAMR1 and SAMP1/TA-1 mice after the first lipopolysac- charide treatment. (A, B) Changes in levels of gene expression of proinflammatory cytokines such as interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF)-α, and inter- feron (IFN)-g; anti-inflammatory cytokines such as IL-10; and IFN-g-inducible chemokines such as Cxcl9 and Cxcl10 in the liver (A) and spleen (B) of SAMR1 and SAMP1/TA-1 mice after the first treatment with lipopolysaccharide (LPS). The expression levels of pro-inflammatory cytokines such as IL-1β (a), IL-6 (b), TNF-α (c), and IFN-γ (d); anti-inflammatory cytokines such as IL-10 (e); and IFN-g-inducible chemokines such as Cxcl9 (f) and Cxcl10 (g) were evaluated in the liver (A) and spleen (B) of SAMR1 and SAMP1/TA-1 mice 1, 3, and 6 h and 1, 2, 3, 5, and 7 days after the first treatment with 25 μg LPS. Each value shown for SAMR1 (closed circles) and SAMP1/TA-1 (open circles) mice after LPS treatment is relative to the level in non-treated control SAMR1 mice. Each bar represents the mean ± standard devi- ation obtained from three mice.
longed overwhelming inflammation occurred in SAMP1/TA-1 mice but not in SAMR1 mice.
Macrophages commonly exist in two distinct subsets, M1 and M2 macrophages, which have opposite functions. M1 macrophages are proinflammatory, and M2 macrophages are anti-inflammatory. The M1/M2 macrophage balance governs the inflammation process.35 LPS treatment resulted in a prolonged increase in the pro- portion of M1 macrophages and simultaneously a decrease in the M2 macrophage proportion in SAMP1/TA- 1 mice on day 5, compared with SAMR1 mice (Figure 8). The proportions of M1 and M2 macrophages were ana- lyzed using peritoneal macrophages, and these data also support the idea that prolonged overwhelming inflamma- tion occurred in SAMP1/TA-1 mice.
In addition, the magnitude of the upregulation of IFN-g in the liver and spleen was greater in SAMP1/TA-1 mice
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haematologica | 2019; 104(10)