Role of neutrophils and Kupffer cells in hepatic cells in hepatic infection: Do we have it wrong?

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Introduction. Systemic infection is localized and cleared by the liver within minutes. Kupffer cells (KCs) are thought to be the critical cell involved in bacterial clearance. Work in this field has been performed with Listeria Monocytogenes, an intracellular pathogen that is not seen often in the clinical setting. This work examines the role of KCs and neutrophils in hepatic clearance of E. coli, an organism that frequently causes sepsis. Methods. C57BL/6 mice were rendered KC-deficient with Gadolinium chloride (Gd) or neutropenic with anti-Ly6 monoclonal antibody therapy. KC depletion was confirmed by demonstrating decreased uptake of colloidal carbon, an agent taken up by KCs, or by immunohistochemistry using F4/80 mAb. Control animals received PBS injection. Specific hepatic infection with various doses (2 × 10 5-10 6) of E. coli was performed by direct injection into the portal vein (PV). Colony counts (CFU) recovered from the liver and peripheral blood, and histology of the liver, were assessed at 10 min and 6 h after infection ( n = 4/grp). Survival was assessed in neutropenic animals ( n = 8/grp). Results. KC depletion did not result in alterations of trapping (at 10 min) or clearance of E. coli in the liver, as measured by bacterial growth. Depletion of neutrophils resulted in similar trapping, but significantly greater bacterial growth by 6 h after infection. Similarly, neutropenia resulted in decreased survival after infection (25% survival neutropenic/100% survival in neutrophil sufficient). Histologic examination revealed the presence of large clusters of neutrophils in KC-depleted animals, but not KC-sufficient animals, at 6 h after infection, suggesting a role for KCs in control of activated neutrophils that are involved in clearance of infection. Conclusions. Surprisingly, KCs appear not to be critical to initial trapping or control of E. coli; by comparison, neutrophils are critical to the elimination of E. coli. KCs are likely important in controlling neutrophils that have emigrated to the liver to control infection. TABLE—ABSTRACT P85 10 minutes 6 hours anti-Ly6 114,800 ± 22,220 137,440 ± 43,507 PBS 78,320 ± 20,436 22,080 ± 4,817 P-value 0.27 0.03