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

Abstract

Murine polymicrobial sepsis is associated with a sustained reduction of dendritic cell (DC) numbers in lymphoid organs and with a dysfunction of DC that is considered to mediate the chronic susceptibility of post-septic mice to secondary infections. We investigated whether polymicrobial sepsis triggered an altered de novo formation and/or differentiation of DC in the bone marrow. BrdU labeling experiments indicated that polymicrobial sepsis did not affect the formation of splenic DC. DC that differentiated from bone marrow (bone marrow-derived DC [BMDC]) of post-septic mice released enhanced levels of IL-10 but did not show an altered phenotype in comparison with BMDC from sham mice. Adoptive transfer experiments of BMDC into naive mice revealed that BMDC from post-septic mice impaired Th1 priming but not Th cell expansion and suppressed the innate immune defense mechanisms against Pseudomonas bacteria in the lung. Accordingly, BMDC from post-septic mice inhibited the release of IFN-γ from NK cells that are critical for the protection against Pseudomonas. Additionally, sepsis was associated with a loss of resident DC in the bone marrow. Depletion of resident DC from bone marrow of sham mice led to the differentiation of BMDC that were impaired in Th1 priming similar to BMDC from post-septic mice. Thus, in response to polymicrobial sepsis, DC precursor cells in the bone marrow developed into regulatory DC that impaired Th1 priming and NK cell activity and mediated immunosuppression. The absence of resident DC in the bone marrow after sepsis might have contributed to the modulation of DC differentiation.

Profound and persistent decrease of circulating dendritic cells is associated with ICU-acquired infection in patients with septic shock

“…The specific role of mDCs in antigen presentation as compared with pDCs suggests that the susceptibility to secondary infection involves an impairment of adaptive immunity. Several experimental studies suggest that quantitative and functional abnormalities of DCs increase susceptibility to secondary infection [28][29][30]. Indeed, polymicrobial sepsis induces persistent functional abnormalities of DCs characterized by impaired maturation, defective activation in response to Toll-like receptors agonists, imbalance between the production of IL-12 and IL-10 thereby skewing the immune response toward a Th-2 pattern, and a defective priming of T cell lymphocytes [30,31].…”

“…Indeed, polymicrobial sepsis induces persistent functional abnormalities of DCs characterized by impaired maturation, defective activation in response to Toll-like receptors agonists, imbalance between the production of IL-12 and IL-10 thereby skewing the immune response toward a Th-2 pattern, and a defective priming of T cell lymphocytes [30,31]. Such functional abnormalities have been linked to increased susceptibility to secondary Pseudomonas aeruginosa pneumonia or invasive aspergillosis [28][29][30]. In humans, few data establish a link between sepsis-induced immunodysfunction and increased susceptibility to nosocomial sepsis.…”

Wnt5a Skews Dendritic Cell Differentiation to an Unconventional Phenotype with Tolerogenic Features

“…Accordingly, Wnt5a might contribute to the attenuation of inflammatory responses or to chronic bacterial infection that negatively affect the function of DCs that differentiate after the onset of the inflammatory process. Likewise, Wnt5a also could be a factor that contributes to the observed dysfunction of DCs that develops during polymicrobial sepsis that impairs the resolution of secondary infections (48). Nevertheless, the local concentrations of soluble inhibitors for Wnt5a or additional and unknown signals produced during the inflammatory process could override Wnt5a-negative effects, allowing normal DC development.…”

Adoptive transfer of naïve dendritic cells in resolving post-sepsis long-term immunosuppression

“…Post-septic changes are not only limited to MOs and wide array of cells is affected. Altered function is also seen in bone marrow precursors, stem cells or mesenchymal cells of bone marrow [7,33]. Likely mechanism triggering these long-term changes is apoptosis.…”

“…Despite the resolution of immediate symptoms of sepsis the survivors continue to have elevated mortality and morbidity comparing to the peers without prior history of sepsis [3]. Increased prevalence of opportunistic infection, higher mortality to subsequent sepsis and increased prevalence of neoplasms are most frequently cited long-term sequels to septic episode [4][5][6][7]. Therefore, the focus in sepsis treatment needs to shift from early goals to long-term outcome [8].…”