Roles of platelets and macrophages in the protective effects of lipopolysaccharide against concanavalin A-induced murine hepatitis

Zhiqian Yu (1, 2) , Hirotada Otsuka (3) , Kouji Yamaguchi (1) , Toshinobu Kuroishi (1) , Takashi Sasano (2) , Shunji Sugawara (1) , Masanori Nakamura (3) , Yasuo Endo (1)

1 Department of Molecular Regulation
2 Department of Oral Diagnosis
3 Department of Oral Anatomy and Developmental Biology

Platelets are reportedly causal in hepatitis. We previously showed that in mice, lipopolysaccharide (LPS) induces a reversible and macrophage-dependent hepatic platelet accumulation (HPA), including translocation of platelets into Disse spaces and their entry into hepatocytes. Concanavalin A (ConA), which induces hepatitis in mice via both T cells and macrophages, also induces HPA. Here, we examined the relationship between HPA and ConA-hepatitis. ConA-hepatitis and HPA were evaluated by serum transaminases, hepatic 5-hydroxytryptamine, and/or electron microscopy. Unlike LPS-induced HPA, ConA-induced HPA was only moderately dependent on phagocytic macrophages. Against expectations, platelet-depletion significantly exacerbated ConA-hepatitis, and anti-P-selectin antibody and P-selectin receptor blockade reduced both ConA-induced HPA and hepatitis. Prior induction of HPA by pretreatment with low-dose LPS powerfully reduced ConA-hepatitis. Such protection by LPS-pretreatment was not effective in mice depleted of phagocytic macrophages. In platelet-depleted mice, LPS-pretreatment severely exacerbated ConA-hepatitis. In mice depleted of both macrophages and platelets, neither ConA nor LPS-pretreatment+ConA induced hepatitis. In mice deficient in IL-1α and IL-1β (but not in TNFα), ConA-induced hepatitis was mild, and a protective effect of LPS was not detected. These results suggest that (i) there are causal and protective types of HPA, (ii) the causal type involves hepatic aggregation of platelets, which may be induced by platelet stimulants leaked from injured hepatocytes, (iii) the protective type is inducible by administration of prior low-dose LPS in a manner dependent on phagocytic (or F4/80-positive) macrophages, and (iv) IL-1 is involved in both the causal and protective types. (within 250 words, now 244)

Mots clés: Macrophage; Platelet; Concanavalin A; Lipopolysaccharide; Liver; Kupffer cells

Domaines: Biochimie, Biologie Moléculaire

Zhiqian Yu, Hirotada Otsuka, Kouji Yamaguchi, Toshinobu Kuroishi, Takashi Sasano, et al.. Roles of platelets and macrophages in the protective effects of lipopolysaccharide against concanavalin A-induced murine hepatitis. Biochimica et Biophysica Acta - Molecular Basis of Disease, 2011, 1812 (9), pp.1069. ⟨10.1016/j.bbadis.2011.06.005⟩. ⟨hal-00719826⟩