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Design of Cecal Ligation and Puncture and Intranasal Infection Dual Model of Sepsis-Induced Immunosuppression
Published on: June 15, 2019
Modulation of dendritic cell differentiation in the bone marrow mediates sustained immunosuppression after
Eva Pastille1, Sonja Didovic, Daniela Brauckmann
1Surgical Research, Department of Trauma Surgery, University Hospital Essen, University Duisburg-Essen, D-45147 Essen, Germany.
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.
Insights
Polymicrobial sepsis induces bone marrow-derived dendritic cells (BMDC) to suppress immune responses, impairing Th1 priming and NK cell activity. This highlights a mechanism for post-sepsis susceptibility to infection.
Area of Science:
- Immunology
- Cell Biology
Background:
- Polymicrobial sepsis causes reduced dendritic cell (DC) numbers and function, leading to chronic susceptibility to secondary infections.
- The role of de novo DC formation and differentiation in the bone marrow following sepsis remains unclear.
Purpose of the Study:
- To investigate if polymicrobial sepsis alters the de novo formation and differentiation of DCs in the bone marrow.
- To understand the functional consequences of sepsis-induced changes in bone marrow-derived DCs (BMDC) on immune responses.
Main Methods:
- Utilized BrdU labeling to assess DC formation in splenic and bone marrow compartments.
- Characterized BMDC from post-septic mice for phenotype and cytokine release (IL-10).
- Performed adoptive transfer of BMDC into naive mice to evaluate their impact on T-cell responses (Th1 priming) and innate immunity (NK cell activity against Pseudomonas).
- Investigated the effect of resident DC depletion in bone marrow on BMDC differentiation and function.
Main Results:
- Sepsis did not affect splenic DC formation but led to a loss of resident DCs in the bone marrow.
- BMDC from post-septic mice exhibited enhanced IL-10 release without significant phenotypic changes.
- Adoptive transfer of post-septic BMDC impaired Th1 priming, suppressed innate immune defense against Pseudomonas, and inhibited IFN-γ release from NK cells.
- Depletion of bone marrow resident DCs mimicked the impaired Th1 priming observed with post-septic BMDC.
Conclusions:
- Polymicrobial sepsis reprograms bone marrow DC precursors into regulatory DCs that suppress Th1 priming and NK cell activity, contributing to immunosuppression.
- The loss of resident DCs in the bone marrow post-sepsis may play a role in modulating DC differentiation and the resulting immune dysfunction.
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