Immunosenescence: A Critical Factor Associated With Organ Injury After Sepsis

Abstract

Progressive immune dysfunction associated with aging is known as immunosenescence. The age-related deterioration of immune function is accompanied by chronic inflammation and microenvironment changes. Immunosenescence can affect both innate and acquired immunity. Sepsis is a systemic inflammatory response that affects parenchymal organs, such as the respiratory system, cardiovascular system, liver, urinary system, and central nervous system, according to the sequential organ failure assessment (SOFA). The initial immune response is characterized by an excess release of inflammatory factors, followed by persistent immune paralysis. Moreover, immunosenescence was found to complement the severity of the immune disorder following sepsis. Furthermore, the immune characteristics associated with sepsis include lymphocytopenia, thymus degeneration, and immunosuppressive cell proliferation, which are very similar to the characteristics of immunosenescence. Therefore, an in-depth understanding of immunosenescence after sepsis and its subsequent effects on the organs may contribute to the development of promising therapeutic strategies. This paper focuses on the characteristics of immunosenescence after sepsis and rigorously analyzes the possible underlying mechanism of action. Based on several recent studies, we summarized the relationship between immunosenescence and sepsis-related organs. We believe that the association between immunosenescence and parenchymal organs might be able to explain the delayed consequences associated with sepsis.

Keywords: immune aging; immunosenescence; immunosuppression; myeloid-derived suppressor cells; sepsis.

Figure 1

Immunosenescence and parenchymal organ damage complement each other. The senescent immune cells (Left) show excessive oxidative stress in the mitochondria. The dysfunction, in turn, leads to DNA damage, telomere attrition, and proteostasis destruction. The cell cycle is inhibited. The senescence-associated secretory phenotype (SASP) is released, and lysosomal SA-β-gal accumulates. Immunosenescence could influence the central nervous system, respiratory system, cardiovascular system, liver, and kidneys (Right). At the same time, the damage to these parenchymal organs may also cause immune senescence.

Figure 2

Immunosuppression and immunosenescence caused by myeloid-derived suppressor cells (MDSCs) after sepsis. Damaged cells and pathogens release damage-associated molecular patterns (DAMPs) and pathogen-associated molecular patterns (PAMPs), respectively, which are picked up by the immune system. During immunosuppression and immunosenescence stage of sepsis, MDSCs are activated and inhibit the function of dendritic cells (DCs) and macrophages. At the same time, MDSCs reduce the diversity of NK cells. Monocytes differentiate into DCs and macrophages, but MDSCs change the cytokines secreted by them. The functions of the T cells and B cells are inhibited by damaged antigen-presenting cells, controlled by MDSCs, and regulated by regulatory T (Treg) cells. Immunosenescence and immunosuppression form a vicious cycle.

Figure 3

The signaling pathways of T cell senescence following sepsis-associated organ injury. The disruption of glucose metabolism activates the PI3K-AkT-mTOR signaling pathways in senescent T cells. The increase of cyclic adenosine monophosphate (cAMP) activates cAMP-PKA-CREB pathway, ERK1/2 and p38 pathways. These pathways may induce DNA damage and cell cycle arrest. The release of damage-associated molecular patterns (DAMPs) activates cGAS-STING pathway and NFκB pathway which may be related to SASP secretion and mitochondrial dysfunction.