Enhanced Dendritic Cell Survival Attenuates Lipopolysaccharide-Induced Immunosuppression and Increases Resistance to Lethal Endotoxic Shock

Abstract

Impaired immune function and associated immunosuppression are hallmarks of septic syndromes. As part of an overall deactivation of the immune system, profound depletion of dendritic cells (DCs) occurs in both septic patients and septic mice. Such depletion of DCs is potentially associated with immunosuppression and with failure to induce a protective Th1 immune response; it may equally be predictive of fatal outcome in septic patients. To evaluate the impact of enhanced DC survival on LPS-induced immunosuppression and on survival after LPS-induced septic shock, we created a transgenic mouse model specifically overexpressing the human form of the antiapoptotic protein Bcl-2 in DCs (DC-hBcl-2 mice). DCs derived from DC-hBcl-2 mice exhibited higher resistance to maturation-induced apoptosis after LPS treatment both in vitro and in vivo. Moreover, prolongation of DC survival diminished sublethal LPS-induced DC loss and immunosuppression, with maintenance of the differentiation potential of Th1 cells and enhanced T cell activation. Such modulation of the immune response appears to constitute a key feature of the attenuated mortality observed after LPS-induced shock in DC-hBcl-2 mice. Our study therefore identifies DC death as a key determinant of endotoxin-induced immunosuppression and mortality in mice.

NFκB2/p100 Is a Key Factor for Endotoxin Tolerance in Human Monocytes: A Demonstration Using Primary Human Monocytes from Patients with Sepsis

“…As we previously reported, a clinically relevant example of ET was observed in patients with sepsis (23,24). Monocytes from these patients exhibit ET (2,4,23,25,26) and fail to produce proinflammatory cytokines after an ex vivo LPS challenge (1,2,4,25).…”

Caspase-7 deficiency protects from endotoxin-induced lymphocyte apoptosis and improves survival

“…Lethal endotoxemia is a widely used experimental model that mimics many features of septic shock, including elevated cytokine production and extensive leukocyte apoptosis. 8,20 However, it is currently not well understood which caspases contribute to endotoxemia-associated lymphocyte apoptosis. To study whether caspase-7 was implicated in endotoxininduced lymphocyte apoptosis, spleens of caspase-7 ϩ/ϩ and caspase-7 Ϫ/Ϫ mice were collected 24 hours after intraperitoneal LPS injection (20 mg kg Ϫ1 ).…”

“…[4][5][6][7][8] In this regard, synthetic caspase inhibitors and overexpression of the antiapoptotic protein Bcl-2 were shown to diminish lymphocyte apoptosis and improve survival in experimental sepsis models. [8][9][10][11][12] However, it is currently incompletely understood which caspases promote lymphocyte apoptosis and contribute to lethality.Together with caspase-3, the executioner caspase-7 performs central roles in the execution phase of apoptosis by cleaving a large set of substrates, ultimately resulting in the morphologic and biochemical hallmarks of apoptosis such as DNA fragmentation. [13][14][15][16] Caspase-3/-7 double-deficient mice were recently shown to exhibit embryonic lethality, whereas mice singly deficient in either caspase are born at normal Mendelian ratios and display no gross abnormalities when maintained on a C57BL/6 genetic background.…”

Endotoxin Tolerance as a Key Mechanism for Immunosuppression

“…In line with this, LPS-tolerant macrophages were found to have reduced apoptosis compared to naive macrophages, during polymicrobial sepsis. Depletion of DCs has been noted in human and mice sepsis (Hotchkiss et al, 2002;Efron et al, 2004), whereas, increased DC survival in mice stimulates resistance to endotoxin shock and attenuate LPS-induced immunosuppression (Gautier et al, 2008). Although, the role of apoptosis in ET still warrants investigation, the evidence at hand emphasize the importance of immune cell apoptosis in mediating sepsis-induced immunosuppression.…”