Contribution of Dendritic Cell Responses to Sepsis-Induced Immunosuppression and to Susceptibility to Secondary Pneumonia

Abstract

Dendritic cells (DCs) are bone marrow derived cells which continuously seed in peripheral tissue. During infection, DCs play an essential interface between innate and adaptive immunity. Pneumonia is a lung inflammation triggered by pathogens and is characterized by excessive release of inflammatory cytokines that activate innate and acquired immunity. Pneumonia induces a rapid and protracted state of susceptibility to secondary infection, a state so-called sepsis-induced immunosuppression. In this review, we focus on the role of DCs in the development of this state of immunosuppression. Early during inflammation, activated DCs are characterized by decreased capacity of antigen (cross)- presentation of newly encountered antigens and decreased production of immunogenic cytokines, and sepsis-induced immunosuppression is mainly explained by a depletion of immature DCs which had all become mature. At a later stage, newly formed respiratory immature DCs are locally programmed by an immunological scare left-over by inflammation to induce tolerance. Tolerogenic Blimp1+ DCs produce suppressive cytokines such as tumor growth factor-B and participate to the maintenance of a local tolerogenic environment notably characterized by accumulation of Treg cells. In mice, the restoration of the immunogenic functions of DCs restores the mucosal immune response to pathogens. In humans, the modulation of inflammation by glucocorticoid during sepsis or trauma preserves DC immunogenic functions and is associated with resistance to secondary pneumonia. Finally, we propose that the alterations of DCs during and after inflammation can be used as biomarkers of susceptibility to secondary pneumonia and are promising therapeutic targets to enhance outcomes of patients with secondary pneumonia.

Keywords: dendritic cells; immunity; inflammation; innate; intensive care units; mucosal immunity; pneumonia; steroids.

Figure 1

Migratory dendritic cell response during primary pneumonia, and during sepsis-induced immunosuppression (left). The stimulation of immature migratory dendritic cells (im.DCs) by pathogen-associated molecular patterns induces the production of inflammatory cytokines (such as Interleukin-12) which stimulate innate-like lymphocyte and natural killer cell (NK) functions and primes naive CD4 T cells. During sepsis-induced immunosuppression (middle and right panels), bacterial clearance is decreased as compared to what is observed during primary pneumonia. (middle) Early after primary infection, activated DCs (Act.DCs) are unable to respond to subsequent pathogens, and fail to produce cytokines and prime new CD4 T cells. (right) Lately, newly formed DCs locally acquire a tolerogenic programing (Tol. DCs) upon instruction by local tolerogenic mediators (star). Glucocorticoid (GC) inhibits DC activation and limit the SIRS. Upon stimulation by pathogens, Tol-DCs do not activate NK cells but induce the local accumulation of Treg cells. GC inhibits tolerogenic mediators and can restore immunogenic functions of newly formed DCs.