Dendritic Cells Modulate Lung Response toPseudomonas aeruginosain a Murine Model of Sepsis-Induced Immune Dysfunction

Abstract

Host infection by pathogens triggers an innate immune response leading to a systemic inflammatory response, often followed by an immune dysfunction which can favor the emergence of secondary infections. Dendritic cells (DCs) link innate and adaptive immunity and may be centrally involved in the regulation of sepsis-induced immune dysfunction. We assessed the contribution of DCs to lung defense in a murine model of sublethal polymicrobial sepsis (cecal ligature and puncture, CLP). In this model, bone marrow-derived DCs (BMDCs) retained an immature phenotype, associated with decreased capacity of IL-12p70 release and impaired priming of T cell lymphocytes. Eight days after CLP surgery, we induced a secondary pulmonary infection through intratracheal instillation of 5 ؋ 10 6 CFUs of Pseudomonas aeruginosa. Whereas all sham-operated mice survived, 80% of post-CLP mice died after secondary pneumonia. Post-CLP mice exhibited marked lung damage with early recruitment of neutrophils, cytokine imbalance with decreased IL-12p70 production, and increased IL-10 release, but no defective bacterial lung clearance, while systemic bacterial dissemination was almost constant. Concomitant intrapulmonary administration of exogenous BMDCs into post-CLP mice challenged with P. aeruginosa dramatically improved survival. BMDCs did not improve bacterial lung clearance, but delayed neutrophil recruitment, strongly attenuated the early peak of TNF-␣ and restored an adequate Il-12p70/ IL-10 balance in post-CLP mice. Thus, adoptive transfer of BMDCs reversed sepsis-induced immune dysfunction in a relevant model of secondary P. aeruginosa pneumonia. Unexpectedly, the mechanism of action of BMDCs did not involve enhanced antibacterial activity, but occurred by dampening the pulmonary inflammatory response.

Toll-like receptor-4 agonist in post-haemorrhage pneumonia: role of dendritic and natural killer cells

“…We have reported that haemorrhage did not alter the lung bacterial clearance (phagocyte cells), but increased spleen bacterial burden (adaptive immune response). This paradox was also described in a murine model of sepsis-induced immune dysfunction [15]. Several hypotheses could explain this discrepancy between local and systemic bacterial clearance.…”

“…Lung inflammation and phagocyte recruitment are modulated by cDCs and pDCs in murine models of sepsis [15] or haemorrhage [16]. Three main subsets of splenic DCs have been described in mice: CD8+ cDCs orientate the adaptive immune response toward an inflammatory response and produce large amounts of IL-12; CD8-cDCs exhibit an anti-inflammatory action through IL-10 production; and pDCs are specialised in IFN-a secretion [4].…”

Modulation of Dendritic Cell Differentiation in the Bone Marrow Mediates Sustained Immunosuppression after Polymicrobial Sepsis

“…Therefore, we assume that the sepsis-induced development of DC dysfunction originates in the cells of the hematopoietic compartment. Pène et al (17) recently reported that BMDC generated from post-septic C57BL/6 mice in comparison with BMDC from sham mice weakly expressed MHC class II and costimulatory molecules and were impaired in IL-12 secretion, whereas the formation of IL-10 remained unchanged. These data are in striking contrast to our findings generated with cells from BALB/c mice as well as from C57BL/6 mice (data not shown) and therefore cannot be explained with the use of different mouse strains.…”

“…Previous studies on post-septic DC dysfunction used a CLP protocol that induced sepsis in combination with an antibiotic treatment (16)(17)(18). Because antibiotics are considered to modulate bone marrow cells (21) and therefore might interfere with our studies on DC development, we set up a CLP protocol that induced a less severe sepsis and that, therefore, was independent from an antibiotic treatment.…”

“…The dysfunction of splenic DC during acute sepsis develops into a chronic dysfunction that is maintained even after resolution of the primary infection and is associated with an impaired capacity of DC to drive an effective Th1 response (15,16). Previous studies have shown that post-septic mice can be rescued from lethal secondary infections by a treatment with DC from naive mice (16)(17)(18). These findings led to the assumption that the enhanced susceptibility of post-septic mice to secondary infections is mediated by the chronic dysfunction of DC.…”