The significance and regulatory mechanisms of innate immune cells in the development of sepsis

Abstract

Sepsis with subsequent multiple organ dysfunction is a pronounced systemic inflammatory response to concealed or known infection and is a leading cause of death in intensive care units. The survival rate of severe sepsis and septic shock has not markedly improved in recent decades despite a great number of receptors and molecules involved in its pathogenesis have been found and taken as therapeutic targets. It is essential to thoroughly understand the host cell-mediated immunity involved in the development of sepsis and sepsis-related organ injury. Recent studies indicate that innate immune cells (such as neutrophils, macrophages, dendritic cells, T lymphocytes, regulatory T cells, and natural killer T cells) play pivotal roles in the maintenance of peripheral homeostasis and regulation of immune responses during sepsis. Therefore, an understanding of the biological significance and pathophysiological roles of different cell populations might gain novel insights into the immunoregulatory mechanisms of sepsis. In this review, we focus on major immune cells that may play potential roles in the contribution of new therapeutic approaches for sepsis.

FIG. 1.

The intercommunication of the regulatory T cells, DCs, and NKT cells. (A) The initiation of cognate interactions between autoreactive T and B cells and the establishment of a B and T cell-dependent reaction, the production of cytokines (eg, IL-4, IL-6, IL-10, IFN-γ, TGF-β, etc.) were involved, in turn promoting the activation of Treg. (B) The production of Treg or effector T lymphocytes induced by DCs depended on the immature status, referring to the ratio of immature DCs and mature DCs. Cytokines released by regulatory DCs (immature DCs) might affect the immune activity, and exert immunoregulatory effects. (C) NKT cells possess more similarities to Tregs than other cells. The activation of NKT cells was directly enhanced by certain ligands, but also indirectly through activation of Tregs by cytokines secretion, and NKT cells influenced other T cell functions via regulation of their cytokine responses. DC, dendritic cell; NKT cell, natural killer T cell; IFN-γ, interferon-γ; TGF-β, transforming growth factor-β; Tregs, regulatory T cells; IL, interleukin.

FIG. 2.

Regulation of innate and adaptive immunity by TIPE2 in T cells. The c-Jun N-terminal kinase (JNK), p38 and NF-κB pathways were found to be regulated by the TIPE2 action in T cells. TIPE2 can inhibit activation of AP-1 and NF-κB, and it is also an essential negative regulator of TLR and T cell receptor signal activation. In addition, TIPE2 may significantly enhance the immune suppressive activity in Tregs via influencing the levels of cytokines and receptors. NF-κB, nuclear factor-κB; TIPE2, TNF-α induced protein 8 like-2; TLR, Toll-like receptors.

FIG. 3.

The immunoregulatory effect of immune cells in different phases of sepsis. (A) In the early phase of sepsis, macrophages, DCs, T lymphocytes, Tregs, and NKT cells play pivotal roles in the maintenance of peripheral homeostasis and regulation of inflammatory response by releasing various pro-inflammatory cytokines, including TNF-α and INF-γ. NKT cells also possess cytotoxic effector activity via Fas/Fas ligand and perforin pathway. (B) In the later phase of sepsis, inhibitory cytokines ensued, including IL-10 and IL-4, which limit the strength of immune cell activation and expansion and negatively modulate inflammation. In addition, extracellular HMGB1 has been shown to be able to provoke inflammation, to regulate functions of macrophage and T lymphocytes, and to mediate immune function of DCs and Tregs. HMGB1, high mobility group box-1 protein; TNF-α, tumor necrosis factor-α.