Neutrophils Sequestered in the Liver Suppress the Proinflammatory Response of Kupffer Cells to Systemic Bacterial Infection

Abstract

The liver plays a major role in clearing bacteria from the bloodstream. Rapid clearance is primarily the function of fixed tissue macrophages (Kupffer cells) that line the hepatic sinusoids. Although Kupffer cells play a critical role in blood clearance, the actual elimination of the bulk of bacteria taken up by the liver depends upon the accumulation of bactericidal neutrophils. Subsequent experiments demonstrating neutrophils inside Kupffer cells derived from infected animals prompted our speculation that neutrophils modulate the proinflammatory response of Kupffer cells to bacteria cleared from the bloodstream. Indeed, we report here that neutrophils accumulated in the liver sinusoids suppress cytokine and chemokine mRNA expression and protein production by Kupffer cells. Using listeriosis in mice as an experimental model, we found that IL-1β, IL-6, IL-10, IL-12, TNF-α, MIP-1α, keratinocyte-derived chemokine, and MCP-1 mRNA levels were ≥10-fold more in the livers of Listeria-infected, relative to noninfected control, mice at 0.5–2 h after i.v. infection. Most message levels were sharply diminished thereafter, correlating inversely with increased neutrophil sequestration. Relative to intact animals, mice rendered neutrophil deficient exhibited marked increases in cytokine/chemokine mRNA expression and protein production in the liver subsequent to infection. Moreover, purified Kupffer cells derived from infected, neutrophil-depleted mice produced significantly more IL-6, IL-10, IL-12, TNF-α, keratinocyte-derived chemokine, and MCP-1 in culture. These findings document the critical role of neutrophils in moderating the proinflammatory response of Kupffer cells to bacteria taken up by the liver.

Neutrophil IL-10 suppresses peritoneal inflammatory monocytes during polymicrobial sepsis

“…Neutrophils have demonstrated regulatory properties in the setting of hemorrhagic shock by down-regulating IL-6 within the liver and lungs [36]. Neutrophils are recognized as being able to modulate macrophages in sterile inflammation and single pathogen infection models [37,38], but the effects of neutrophils on inflammatory monocytes have not been reported previously. Daley et al [37] showed elevated levels of TNF and superoxide anion release from wound macrophages when neutrophils and presumably inflammatory monocytes were depleted with ␣Gr1 in the polyvinyl alcohol sponge wound model of inflammation.…”

“…It is well established that ingestion of apoptotic cells can suppress the proinflammatory phenotype of effector immune cells, including macrophages [40 -43]. In a model of systemic listeriosis, Holub et al [38] demonstrated that apoptotic neutrophils suppressed the proinflammatory response after being ingested by Kupffer cells. Neutrophils are short-lived cells with a halflife of 6 -10 h and upon activation, undergo spontaneous apoptosis [44].…”

The evolving story of macrophages in acute liver failure

“…Bacteria engulfed by KCs are then internalized and killed by neutrophils through adhesion molecules CD11b/CD18 and CD54. The rapid elimination of bacteria as a result of a close interaction between KCs and neutrophils is apparently beneficial to liver host defenses [88,89]. In endotoxin-associated or ischemia/reperfusion liver injury, production of TNF-␣ or cytokine-induced neutrophil chemoattractant (CINC) by KCs has been shown to contribute to neutrophil adhesion and infiltration into hepatic sinusoids [90,91].…”

Distinct CCR2+Gr1+Cells Control Growth of theYersinia pestisΔyopMMutant in Liver and Spleen during Systemic Plague

“…YopM could indirectly influence production of chemokines that signal through CCR2 in spleen by downregulating expression of cytokines, such as IL-1␤ and TNF-␣ (25), that activate ECs (33,45) Liver structure, function, and response to infection are distinct from those in spleen (23,40). In liver sinusoids, Kupffer cells (KCs) and neutrophil-KC interactions are prominent in the response to bacterial infection (16,17,20). KCs themselves are not potent antibacterial cells, but they bind bacteria avidly and present them to PMNs for killing (15)(16)(17)29).…”