Abstract
Sepsis is the dysregulated response of the host to systemic, mostly bacterial infection, and is associated with an enhanced susceptibility to life-threatening opportunistic infections. During polymicrobial sepsis, dendritic cells (DCs) secrete enhanced levels of interleukin (IL) 10 due to an altered differentiation in the bone marrow and contribute to the development of immunosuppression. We investigated the origin of the altered DC differentiation using murine cecal ligation and puncture (CLP), a model for human polymicrobial sepsis. Bone marrow cells (BMC) were isolated after sham or CLP operation, the cellular composition was analyzed, and bone marrow-derived DCs (BMDCs) were generated in vitro. From 24 h on after CLP, BMC gave rise to BMDC that released enhanced levels of IL-10. In parallel, a population of CD11chiMHCII+CD4+ DCs expanded in the bone marrow in a MyD88-dependent manner. Prior depletion of the CD11chiMHCII+CD4+ DCs from BMC in vitro reversed the increased IL-10 secretion of subsequently differentiating BMDC. The expansion of the CD11chiMHCII+CD4+ DC population in the bone marrow after CLP required the function of sphingosine 1-phosphate receptors and C-C chemokine receptor (CCR) 2, the receptor for C-C chemokine ligand (CCL) 2, but was not associated with monocyte mobilization. CD11chiMHCII+CD4+ DCs were identified as plasmacytoid DCs (pDCs) that had acquired an activated phenotype according to their increased expression of MHC class II and CD86. A redistribution of CD4+ pDCs from MHC class II− to MHC class II+ cells concomitant with enhanced expression of CD11c finally led to the rise in the number of CD11chiMHCII+CD4+ DCs. Enhanced levels of CCL2 were found in the bone marrow of septic mice and the inhibition of CCR2 dampened the expression of CD86 on CD4+ pDCs after CLP in vitro. Depletion of pDCs reversed the bias of splenic DCs toward increased IL-10 synthesis after CLP in vivo. Thus, during polymicrobial sepsis, CD4+ pDCs are activated in the bone marrow and induce functional reprogramming of differentiating BMDC toward an immunosuppressive phenotype.
Highlights
Dendritic cells (DCs) are professional antigen-presenting cells and are present in lymphoid and non-lymphoid tissues where they serve as “sentinels” of the immune system
We have previously shown that Bone marrow cells (BMCs) from septic mice when cultured in the presence of granulocyte/macrophage-colony-stimulating factor (GM-CSF) in vitro give rise to bone marrow-derived dendritic cells (BMDCs) that resemble splenic DCs during sepsis in terms of increased IL-10 synthesis [29]
Bone marrow cell cultures in the presence of GM-CSF mimic the differentiation of DCs under inflammatory conditions
Summary
Dendritic cells (DCs) are professional antigen-presenting cells and are present in lymphoid and non-lymphoid tissues where they serve as “sentinels” of the immune system. Diverse subsets of DCs exist: conventional DCs characteristically express high levels of CD11c along with major histocompatibility complex (MHC) class II and co-stimulatory molecules that are strongly increased during bacterial infection [1]. Th1 and NK cells secrete interferon (IFN) γ that increases the bactericidal activity of phagocytes and thereby supports the elimination of the pathogens [4]. Due to their capacity to orchestrate the collaboration of immune cells, DCs play a decisive role in the defense against numerous bacterial infections. PDCs increase their expression of MHC class II and co-stimulatory molecules, may release diverse cytokines and chemokines, and become potent antigenpresenting cells [8, 9]
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