Abstract 16825: Macrophage Sensing of Lps in vivo is Not Required for the Induction of Systemic Inflammation
Introduction: The traditional view of the immune system has macrophages playing a pivotal role in the sensing of bacteria and subsequent initiation of an inflammatory response. However, the discovery of pattern recognition receptors, such as Toll like receptors (TLR), has revolutionised our understanding of immunity. TLRs allow specificity in the recognition of pathogen associated molecular patterns (PAMPs): Bacterial lipopolysaccharide (LPS) is recognized by the TLR4/CD14/MD2 receptor complex. TLRs are widely distributed in mammalian tissues, including tissues that are not classically thought to play role in immune sensing, such as blood vessels. Despite evidence that heart tissue and blood vessels can sense pathogens directly, the current dogma suggests that haemopoietic cells, principally macrophages, are the sensing tissue of LPS in vivo.
Hypothesis: Using reciprocal TLR bone marrow chimaeras, we assessed the hypothesis that sensing of LPS in vivo is not entirely dependent on haemopoetic tissues, and animals with macrophages deficient of TLR4 can mount a systemic inflammatory response to LPS.
Methods and results: In wild type mice (WT◊WT) or in wild type mice with TLR4 deficient bone marrow (KO◊WT), LPS (6mg/kg) induced hypothermia, which followed the predicted slow onset time course. LPS did not induce hypothermia in TLR4 deficient recipients with TLR4 deficient bone marrow (KO◊KO) or in TLR4 deficient recipients with wild type bone marrow (WT◊KO). LPS induced increases in plasma nitrite and vascular hyporeactivity in all groups of mice except KO◊KO. GMC-SF, INFγ, IL-10, IL-1, IL-6, KC and TNFα levels were all elevated in WT◊WT, but not in KO◊KO mice. For IL-6 and KC, levels were higher in KO◊WT than WT◊KO mice, whilst INFγ levels were higher in WT◊KO than in KO◊WT mice. Lung injury induced by LPS was absent in KO◊KO mice, but persisted in WT◊KO or KO◊WT mice. LPS induced leucopenia and lymphopenia in all groups of mice except KO◊KO mice.
Conclusions: In conclusion, LPS induces systemic effects via resident cell sensing in the absence of TLR4 on bone marrow derived cells.
- © 2010 by American Heart Association, Inc.