Lipopolysaccharide Clearance, Bacterial Clearance, and Systemic Inflammatory Responses Are Regulated by Cell Type–Specific Functions of TLR4 during Sepsis

Abstract

The morbidity associated with bacterial sepsis is the result of host immune responses to pathogens, which are dependent on pathogen recognition by pattern recognition receptors, such as TLR4. TLR4 is expressed on a range of cell types, yet the mechanisms by which cell-specific functions of TLR4 lead to an integrated sepsis response are poorly understood. To address this, we generated mice in which TLR4 was specifically deleted from myeloid cells (LysMTLR4KO) or hepatocytes (HCTLR4KO) and then determined survival, bacterial counts, host inflammatory responses, and organ injury in a model of cecal ligation and puncture (CLP), with or without antibiotics. LysM-TLR4 was required for phagocytosis and efficient bacterial clearance in the absence of antibiotics. Survival, the magnitude of the systemic and local inflammatory responses, and liver damage were associated with bacterial levels. HCTLR4 was required for efficient LPS clearance from the circulation, and deletion of HCTLR4 was associated with enhanced macrophage phagocytosis, lower bacterial levels, and improved survival in CLP without antibiotics. Antibiotic administration during CLP revealed an important role for hepatocyte LPS clearance in limiting sepsis-induced inflammation and organ injury. Our work defines cell type–selective roles for TLR4 in coordinating complex immune responses to bacterial sepsis and suggests that future strategies for modulating microbial molecule recognition should account for varying roles of pattern recognition receptors in multiple cell populations.

Activation of Hepatic STAT3 Maintains Pulmonary Defense during Endotoxemia

“…Yet we observed no differences in killing with or without hepatocyte STAT3, suggesting that either (i) liver STAT3 deficiency (in the setting of endotoxemia) is insufficient to compromise the antibacterial function of an otherwise unchallenged (no pneumonia) alveolar macrophage or (ii) differences in bacterial killing are beyond the detection limit of this experimental system, perhaps due to the small amounts of bacterial uptake in macrophages from LPS-treated mice. The immunosuppressive effect of endotoxemia on macrophage function is consistent with that seen in other studies (11,49,55). Future investigations are needed to determine whether or how previously established pathways driving sepsis-induced pulmonary immunosuppression are mechanistically linked to STAT3-dependent liver activity.…”

Irinotecan-Induced Gastrointestinal Dysfunction and Pain Are Mediated by Common TLR4-Dependent Mechanisms

“…The failure to show differences at most time points in this study could be explained by evidence suggesting that TLR4 on hepatocytes is required for complete endotoxin clearance (38).…”

Kupffer cells and activation of endothelial TLR4 coordinate neutrophil adhesion within liver sinusoids during endotoxemia

“…However, the liver contains a large population of intravascular macrophages (Kupffer cells) that are intimately involved in many inflammatory and immunological responses in the liver (11) and may also affect neutrophil recruitment during endotoxemia. In fact, an important role for Kupffer cells in the development of sepsis-induced liver inflammation and pathology has previously been reported (13,40). To determine whether Kupffer cells contribute to LPS-induced neutrophil recruitment in liver sinusoids, a group of mice was depleted of Kupffer cells by iv administration of clodronate liposomes (CLL) 48 h prior to LPS injection.…”

“…Within the liver, Kupffer cells are optimally positioned within the vasculature to encounter circulating bacteria and bacterial products and are critical for their clearance from the bloodstream during steady state and during sepsis (11,13,26). Furthermore, Kupffer cells have well-defined roles in the coordination of hepatic inflammation in a number of diseases (11,26,40).…”