Role of macrophages in regeneration of liver

Abstract

In an attempt to clarify the role of macrophages and their mediators during regeneration of the liver, the difference of liver regeneration among C3H/HeN (LPS-responsive strain) and C3H/HeJ (LPS-resistant strain) mice was investigated. After a 67% partial hepatectomy, an increase in the weight of regenerating liver was significantly delayed in the C3H/HeJ mice, as compared with C3H/HeN mice. The number of hepatocytes labeled with antibody against PCNA reached maximum levels 48 hr after partial hepatectomy, but the PCNA labeling index in C3H/HeJ mice was 20% less than that for C3H/HeN mice. In addition, TNF-alpha activities in serum were enhanced shortly after partial hepatectomy in C3H/HeN strain mice, but were not increased in C3H/HeJ strain mice. Serum IL-6 levels were markedly enhanced in both C3H/HeN and C3H/HeJ mice, but a bimodial peak (14 and 48 hr after partial hepatectomy) was demonstrated in C3H/HeN mice, in contrast to a single peak (at 24 hr) in C3H/HeJ mice. Suppression of Kupffer cells by previous administration of gadolinium chloride in C3H/HeN mice reduced the increase in both serum TNF-alpha and IL-6 concentrations, reduced PCNA labeling index of hepatocytes by 20%, and disturbed the regeneration of the liver. Previous administration of antibody against TNF-alpha reduced the PCNA labeling index of hepatocytes by 20% after partial hepatectomy in C3H/HeN strain mice. These results suggest that LPS-responsive macrophages in the liver and their mediators, especially TNF-alpha, could partly play a role in liver regeneration.

Proinflammatory Cytokine Production in Liver Regeneration Is Myd88-Dependent, but Independent of Cd14, Tlr2, and Tlr4

“…Our data from the TLR4 KO mice are particularly surprising in light of published data demonstrating a delay in liver regeneration in C3H/HeJ mice, an inbred strain of mice with a point mutation in Tlr4 (i.e., Tlr4 P712H ) (15,16). Our findings, which are consistent with recent studies by Seki et al (58), suggest that a point mutation in TLR4 has more profound effects on liver regeneration than the loss of the entire receptor.…”

“…Although the importance of leukocytes in liver regeneration (53) is accepted, the impact of a proposed difference in composition of liver leukocytes in C3H/HeJ mice on liver regeneration is unknown. Clearly, any of these hypothetical possibilities would need in vivo experimentation to understand the potency of the mutant TLR4 allele in liver regeneration (15,16). In any case, the data presented here strongly suggest that TLR2 and TLR4 are not involved in the initiation of liver regeneration.…”

“…Rats in which LPS has been depleted by antibiotic administration or other methods display impaired hepatocyte DNA synthesis following PH (14). Liver regeneration is also delayed in athymic nucli mice and C3H/HeJ mice, a naturally occurring strain that is hyporesponsive to LPS (15,16). Hepatocyte DNA synthesis is enhanced if these animals receive LPS 24 h before surgery (15,17).…”

Matrix metalloproteinase 9 modulates collagen matrices and wound repair

“…However, substantial evidence indicates that leukocyte response to acute damage can be essential for the normal healing process (LeBert and Huttenlocher, 2014). Leukocyte recruitment is necessary to limit infection at the site of tissue damage (Nathan, 2006), and macrophage recruitment is required for optimal wound healing through the clearance of cellular debris (Leibovich and Ross, 1975;Li et al, 2012;Martin et al, 2003;Shiratori et al, 1996;Tidball and Wehling-Henricks, 2007;van Furth et al, 1985). Support for an important role for macrophages in wound repair has also been shown during regeneration in both larval zebrafish (Li et al, 2012) and the adult fin (Petrie et al, 2014).…”

NF-κB activation in Kupffer cells after partial hepatectomy

“…In TNFRI knockout mice, activation of NF-B and signal transducer and activator of transcription (STAT)3 is inhibited (33). In normal animals, TNF-␣ and IL-6 expression increase in the blood very quickly after PH (1,29). In TNFRI knockout mice, TNF-␣ also increases, but only a slight change in IL-6 is observed.…”