Sphingosine 1-Phosphate- and C-C Chemokine Receptor 2-Dependent Activation of CD4+ Plasmacytoid Dendritic Cells in the Bone Marrow Contributes to Signs of Sepsis-Induced Immunosuppression

Anna Smirnov; Stephanie Pohlmann; Melanie Nehring; Shafaqat Ali; Ritu Mann-Nüttel; Stefanie Scheu; Anne-Charlotte Antoni; Wiebke Hansen; Manuela Büettner; Miriam J Gardiasch; Astrid M Westendorf; Florian Wirsdörfer; Eva Pastille; Marcel Dudda; Stefanie B Flohé

doi:10.3389/fimmu.2017.01622

Sphingosine 1-Phosphate- and C-C Chemokine Receptor 2-Dependent Activation of CD4⁺ Plasmacytoid Dendritic Cells in the Bone Marrow Contributes to Signs of Sepsis-Induced Immunosuppression

Front Immunol. 2017 Nov 23:8:1622. doi: 10.3389/fimmu.2017.01622. eCollection 2017.

Authors

Anna Smirnov¹, Stephanie Pohlmann¹, Melanie Nehring¹, Shafaqat Ali^{2

3}, Ritu Mann-Nüttel², Stefanie Scheu², Anne-Charlotte Antoni¹, Wiebke Hansen⁴, Manuela Büettner⁵, Miriam J Gardiasch¹, Astrid M Westendorf⁴, Florian Wirsdörfer⁶, Eva Pastille⁴, Marcel Dudda¹, Stefanie B Flohé¹

Affiliations

¹ Department of Orthopedics and Trauma Surgery, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
² Institute of Medical Microbiology and Hospital Hygiene, University of Düsseldorf, Düsseldorf, Germany.
³ Cells in Motion, Cluster of Excellence, University of Münster, Münster, Germany.
⁴ Institute of Medical Microbiology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.
⁵ Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany.
⁶ Medical Faculty, Institute of Cell Biology (Cancer Research), University of Duisburg-Essen, Essen, Germany.

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 CD11c^hiMHCII⁺CD4⁺ DCs expanded in the bone marrow in a MyD88-dependent manner. Prior depletion of the CD11c^hiMHCII⁺CD4⁺ DCs from BMC in vitro reversed the increased IL-10 secretion of subsequently differentiating BMDC. The expansion of the CD11c^hiMHCII⁺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. CD11c^hiMHCII⁺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 CD11c^hiMHCII⁺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.

Keywords: bone marrow; chemokines; dendritic cells; differentiation; immunosuppression; monocytes; polymicrobial sepsis; sphingosine-1 phosphate.