Dendritic Cells in Sepsis: Pathological Alterations and Therapeutic Implications

Abstract

Sepsis is the leading cause of death for critically ill patients in recent years. Dendritic cells (DCs) are important antigen-presenting cells and play a key role in immune response by regulating the innate and adaptive immunity. The number of DCs, the differentiation of monocytes into DCs, and the levels of surface molecules associated with the function of DCs are changed in the development of sepsis. There are many mechanisms involved in the alterations of DCs during sepsis, including the induction of apoptosis, reactive oxygen species generation, activation of the Wnt signaling pathway, epigenetic regulation, and variation in Toll-like receptor-dependent signaling. In this review, we present the classifications of DC subsets and mechanisms involved in the alterations of DCs in sepsis, as well as further discuss the therapeutic strategies targeting DCs in sepsis to improve the aberrant immune response and prolong the life during sepsis progression.

Activation of α7 Nicotinic Acetylcholine Receptor Upregulates HLA-DR and Macrophage Receptors: Potential Role in Adaptive Immunity and in Preventing Immunosuppression

“…Low doses of nicotine enhanced the expression of costimulatory molecules CD80, CD40, CD54 and HLA-DR in imDC. DCs are professional antigen-presenting cells [58] that play an important role in the aberrant immune response in sepsis [59,60]. Thus, through the activation of α7 nAChR it becomes possible to regulate several membrane markers involved in the T-cell interaction and antigen presentation.…”

“…Usually, therapeutic strategies for the treatment of sepsis are aimed at suppressing the early phase of the hyperinflammatory response [75]. However, the immunosuppression state exists simultaneously with the persistent inflammation and contributes to the development of persistent, recurrent, secondary and nosocomial infections, which lead to poorer outcomes and increased mortality [59]. While therapeutic attention has long been focused on anti-inflammatory strategies, an increased understanding of the importance of sepsis-induced immune depletion in morbidity and mortality in patients with sepsis has led to a paradigm shift in sepsis research toward strategies to enhance the immune response [76].…”

Crosstalk between Dendritic Cells and Immune Modulatory Agents against Sepsis

“…Strategies focused on inhibiting the dysfunction of DCs could increase survival in sepsis. Administration of DCs can efficiently arrest the induction of the immune suppression function of the residual DCs in septic mice, it diminished the proliferation and differentiation of Treg cells and suppressor T cells via a combination of factors like indoleamine 2,3 deoxygenase (IDO) and IL-10, enhanced the immune clearance of sepsis-causing pathogens, and eventually reduced organ damage, thereby improving the therapy effect [130,131]. A few immunotherapies that aimed to enhance DCs' function have been shown to be capable of mitigating the disease symptoms.…”

Repositioning of the antipsychotic drug TFP for sepsis treatment

“…Therefore, at the early stage of inflammation, the activated DCs induce immunosuppression reducing pro-inflammatory cytokine production [ 3 ]. In sepsis, since the release of the initial inflammatory cytokine causes cytokine storm and eventually results in death due to loss of organ functions such as lung injection, recent studies emphasized the importance of DC, which improve the aberrant immune response and prolong the life during sepsis progression, in the therapeutic strategy target [ 4 , 5 ]. To date, a large number of therapeutic agents have been developed to treat sepsis, such as antibodies against lipopolysaccharides (LPS), toll-like receptor 4 (TLR4) agonists, antitumor necrosis factor (TNF) agents, drugs targeting platelet-activating factor (PAF), and drugs targeting coagulation cascades [ 6 – 8 ].…”