Impact of communication of plasmacytoid dendritic cells and dendritic cell progenitors in the bone marrow during sepsis-induced immune dysregulation

• Applicants: Professorin Dr. Stefanie Flohé; Professorin Dr. Stefanie Scheu
• Subject Area: Orthopaedics, Traumatology, Reconstructive Surgery
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 465743247

Sepsis caused by systemic bacterial infection induces chronic organ dysfunction and an increased risk for secondary infections due to a dysregulation of the immune system. The mechanisms underlying the development of this immune dysregulation are incompletely understood. Recent findings point to a profound epigenetic and metabolic reprogramming in immune and parenchymal cells. Using the murine cecal ligation and puncture (CLP) model for human polymicrobial sepsis we have previously shown that during sepsis conventional dendritic cells (cDCs) undergo a functional reprogramming. These cDCs lose the capacity to secrete interleukin (IL) 12 in response to stimulation with microbial agents and, instead, produce the anti-inflammatory mediator IL-10. The functional reprogramming of cDCs during sepsis originates in an altered differentiation in the bone marrow (BM) as BM-derived DCs from septic mice are impaired in T helper cell type 1 priming. Adoptive transfer of these septic BM-derived DCs into naïve mice increases the susceptibility to Pseudomonas aeruginosa-induced pneumonia. Also, in the BM of septic mice a strong decline in the number of DC progenitor cells (pre-DCs) was detectable that coincided with an altered distribution of terminally differentiated cDC subpopulations in secondary lymphoid organs. We recently showed that a so far unrecognized population of activated CD4+ plasmacytoid DCs (pDCs) that express high levels of CD11c and MHC class II molecules and appear in the BM of septic mice in a CC chemokine receptor (CCR) 2-dependent manner are critically involved the functional reprogramming of cDCs. Preliminary work points to a CXC chemokine receptor (CXCR) 4/Toll-like receptor (TLR) 2-dependent axis between the peritoneal cavity (site of sepsis induction) and the BM as the origin of pDC activation. The aim of the proposed study is to elucidate the mechanisms underlying the appearance of activated CD4+ pDCs in the BM during sepsis and their impact on cDC progenitor cells regarding the differentiation, subset commitment and function. Sepsis-specific changes in phenotype and function of pDCs, pre-DCs, and cDC subsets will be investigated by epigenetic and metabolic signature analyses, transcriptomics, and flow cytometry. CCR2-derived signals in the BM vs. CXCR4/TLR2-mediated signals originating in the peritoneal cavity and their role in the accumulation of CD4+ pDCs in the BM will be defined. In parallel, changes in cDC differentiation and the impact of activated pDCs herein will be elucidated in vivo as will be a role of cDCs in organ dysfunction. In a translational approach, circulating human pDCs and cDCs from septic patients will be interrogated for sepsis-specific expression patterns identified in the murine sepsis model. Deciphering the communication signals between pDCs and pre-DCs will increase our understanding of the development of sepsis-induced immune dysregulation aiming to advance treatment strategies.

• DFG Programme: Research Grants