In vivo Lipopolysaccharide Tolerance Recruits CD11b⁺ Macrophages to the Liver with Enhanced Bactericidal Activity and Low Tumor Necrosis Factor-Releasing Capability, Resulting in Drastic Resistance to Lethal Septicemia

Abstract

Objectives: In vivo lipopolysaccharide (LPS) tolerance on bacterial infection was investigated, focusing on liver macrophages. Methods: LPS tolerance was induced by intraperitoneal injections with 5 μg/kg of LPS for 3 consecutive days, and then mice were intravenously infected with Escherichia coli. Results: All LPS-primed mice survived lethal bacterial infection. Drastic enhancement of bactericidal activity of liver macrophages strongly contributed to bacterial clearance. Although LPS-primed mice produced substantial amounts of tumor necrosis factor (TNF) inside the liver, TNF efflux into the systemic circulation was markedly suppressed. These mice showed a dramatic increase in CD11b⁺ monocyte- derived macrophages in the liver. The CD11b⁺ macrophages that increased in LPS-primed mice were those with strong phagocytic/bactericidal activity and an upregulated expression of Fcγ receptor I, but the subfraction with a potent TNF-producing capacity and poor phagocytic activity diminished. The adoptive transfer of CD11b⁺ macrophages from LPS-primed mice to control mice increased survival after bacterial infection and reduced the elevation of plasma TNF. LPS priming did not affect the CD68⁺ resident Kupffer cells, and CD68⁺ Kupffer cell-depleted mice still exhibited LPS tolerance with strong resistance to bacteremia. Conclusions: LPS tolerance recruits CD11b⁺ macrophages to the liver with enhanced bactericidal activity, which plays a central role in resistance to lethal bacteremia.

Macrophages in the Aging Liver and Age-Related Liver Disease

“…The use of these differentiating markers has been expanded to several disease models, identifying a damaging role of TNF/FasL production by CD11b + mMØs in carbon-tetrachloride acute liver injury and hepatitis in hypercholesterolemic mice ( 58 , 59 ). The CD11b + mMØs were also found to accumulate in the liver following repeated lipopolysaccharide injections, but suppressed TNF efflux into the systemic circulation, thereby reducing lethal septicemia ( 60 ). In addition, the CD11b + mMØs were recruited during diet-induced steatohepatitis in FGF5 deficient mice and following partial hepatectomy, where they were crucial for liver regeneration ( 61 , 62 ).…”

The nuclear variant of bone morphogenetic protein 2 (nBMP2) is expressed in macrophages and alters calcium response

“…We cannot rule out the possibility that the bead engulfment assay did not fully reflect the severity of phagocytosis impairment in splenic macrophages. Liver macrophages also play a role in bacterial clearance, and it is possible that the absence of nBMP2 in the nucleus affects their function more severely 44,45 . In addition, the absence of nBMP2 in the nucleus might affect other immune system cell types besides macrophages, and it is possible that another cell type, or perhaps several cell types together, account for the increased mortality of nBmp2NLS tm mutant mice after secondary infection 3 .…”

Addressing Nanomaterial Immunosafety by Evaluating Innate Immunity across Living Species

“…Humans are highly sensitive to LPS and respond to 1000× lower LPS concentrations compared to mice. [210,211] Careful and reliable detection of potential endotoxin contamination of NM is therefore crucial, especially in the fields of immunology, drug development, and drug delivery. [212,213] This also applies to NM synthesis.…”