Abstract
Administration of heat-killed Propionibacterium acnes renders mice highly susceptible to LPS. After LPS challenge P. acnes-primed mice promptly show hypothermia, hypercoagulation (disseminated intravascular coagulation), elevation of serum proinflammatory cytokine levels, and high mortality. The surviving mice develop liver injury. As previously reported, IL-18 plays a pivotal role in the development of this liver injury. Many cell types including macrophages constitutively store IL-18 as biologically inactive precursor (pro) form. Upon appropriate stimulation exemplified by TLR4 engagement, the cells secrete biologically active IL-18 by cleaving pro-IL-18 with caspase-1. Caspase-1 is also constitutively produced as a zymogen in macrophages. Recently, NLRP3, a cytoplasmic pathogen sensor, has been demonstrated to be involved in the activation of caspase-1. Here, we review the molecular mechanisms for the liver injuries, particularly focusing on the TLR4/NLRP3-mediated caspase-1 activation process, with a brief introduction of the mechanism underlying P. acnes-induced sensitization to LPS.
Highlights
TLR, topics of this issue, is an extracellular sensor family of pathogen-associated molecular patterns (PAMPs) [1, 2]
As described by Yamamoto et al in this special issue, TLR1, TLR2, TLR4, TLR5, TLR6, and TLR11 are expressed on the cell surface, while TLR3, TLR7, TLR8, and TLR9 are expressed on the membrane of endosome, which is a transport vesicle originated from the cell membrane to trap and transport the extracellular macromolecules into the inside of the cells
The NLRP3 inflammasome activation is necessary for the TLR4-mediated casapse-1 activation (Table 3, Figure 7). These results cannot exclude the possibility that the TRIF-mediated pathway might cause extracellular release of ATP and that this self-derived ATP might activate the NLRP3 inflammasome in LPS-stimulated Kupffer cells [57, 58]
Summary
TLR, topics of this issue, is an extracellular sensor family of pathogen-associated molecular patterns (PAMPs) [1, 2]. Splenic macrophages from P. acnes-primed mice produce much higher levels of proinflammatory cytokines including TNF-α in response to LPS than do those from naıve mice [32] This is the case for Kupffer cells. Depletion of macrophages rescues P. acnes-primed mice from the liver injury and high mortality induced by the subsequent challenge with LPS [38] (Table 1). This clearly demonstrates the indispensability of macrophages for the P. acnes-induced sensitization to LPS. The P. acnes-primed mice depleted of macrophages show phenotypes similar to naıve mice after LPS challenge [38] They lack liver injury and 100% survive (Table 1). Macrophages are necessarily required for the P. acnes-induced sensitization to LPS
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