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Review
, 10 (10), 782

Pathological Alteration and Therapeutic Implications of Sepsis-Induced Immune Cell Apoptosis

Affiliations
Review

Pathological Alteration and Therapeutic Implications of Sepsis-Induced Immune Cell Apoptosis

Chao Cao et al. Cell Death Dis.

Abstract

Sepsis is a life-threatening organ dysfunction syndrome caused by dysregulated host response to infection that leads to uncontrolled inflammatory response followed by immunosuppression. However, despite the high mortality rate, no specific treatment modality or drugs with high efficacy is available for sepsis to date. Although improved treatment strategies have increased the survival rate during the initial state of excessive inflammatory response, recent trends in sepsis show that mortality occurs at a period of continuous immunosuppressive state in which patients succumb to secondary infections within a few weeks or months due to post-sepsis "immune paralysis." Immune cell alteration induced by uncontrolled apoptosis has been considered a major cause of significant immunosuppression. Particularly, apoptosis of lymphocytes, including innate immune cells and adaptive immune cells, is associated with a higher risk of secondary infections and poor outcomes. Multiple postmortem studies have confirmed that sepsis-induced immune cell apoptosis occurs in all age groups, including neonates, pediatric, and adult patients, and it is considered to be a primary contributing factor to the immunosuppressive pathophysiology of sepsis. Therapeutic perspectives targeting apoptosis through various strategies could improve survival in sepsis. In this review article, we will focus on describing the major apoptosis process of immune cells with respect to physiologic and molecular mechanisms. Further, advances in apoptosis-targeted treatment modalities for sepsis will also be discussed.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1
Fig. 1. Immune response in sepsis.
Early activation of both innate and adaptive immune response is involved in the pathogenesis of sepsis. The peak mortality rates during the early period (top red line) were due to overwhelming inflammatory response, also known as “cytokine storm,” which comprises fever, refractory shock, inadequate resuscitation, and cardiac or pulmonary failure. Meanwhile, mortality at the later period is due to persistent immunosuppression with secondary infections that results in organ injury and/or failure. Although more sophisticated ICU care has improved mortality, patients still die at the later period or after several years owing to the persistent immunosuppression, immune dysfunction, or chronic catabolism
Fig. 2
Fig. 2. Alterations in innate and adaptive immunity in the pathophysiology of sepsis.
Early activation of innate immunity is the first line of defense against infection and plays a central role in the initiation of adaptive immunity. However, in sepsis, excessive immune responses lead to several alterations in innate and adaptive immunity that contribute to protracted immunosuppression and increase the risk for opportunistic infection. In some way, sepsis can be considered as a race to the death between host immune response and pathogens that seek an advantage by impairing the host immune defenses
Fig. 3
Fig. 3. Sepsis alters innate and adaptive immune cells.
Sepsis-induced immune paralysis is characterized by immunological defects that impair host immunity. Lymphoid cell loss, often resulting in the diminished capacity to fight and eliminate pathogens, is a primary feature of immune suppression during sepsis. Altered immune cell function induced by uncontrolled apoptosis is a major cause of profound immunosuppression. Lymphocyte apoptosis, including that of innate immune cells and adaptive immune cells, is associated with a higher risk of secondary infections and poor outcome in various diseases. As shown here, sepsis rapidly triggers profound apoptosis in macrophages/monocytes, dendritic cells, NK cells, γδ T cells, CD4+ T cells, and B cells. However, apoptosis of neutrophils is delayed, and Treg cells are more resistant to sepsis-induced apoptosis. Immune cell depletion due to apoptosis is the primary mechanism of sepsis-induced immune suppression
Fig. 4
Fig. 4. Sepsis-induced delayed apoptosis and recruitment of neutrophils into tissues lead to multiple organ dysfunction syndrome.
The apoptosis of neutrophils is delayed during the first 24 h after the initiation of sepsis. Then neutrophils are recruited and infiltrate into tissues, aggravating the ongoing neutrophil dysfunction with persistent immune dysfunction and inflammation persistence. Neutrophil infiltration in the lungs is a pathological hallmark of sepsis-induced acute lung injury or acute respiratory distress syndrome as well as of organ dysfunction in the liver and heart. Representative histological changes in tissues are shown in hematoxylin and eosin-stained samples (original magnification ×400). Arrows denote the recruitment and infiltration of neutrophils into tissues

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