From immune dysregulation to organ dysfunction: understanding the enigma of Sepsis

Abstract

Sepsis is a syndrome precipitated by immune dysregulation in response to infection, and represents a pivotal factor in global mortality attributed to diseases. The recent consensus delineates sepsis as a perilous state of organ dysfunction arising from the host's maladaptive reaction to infection. It masks the complexity and breadth of the immune mechanisms involved in sepsis, which is characterized by simultaneous hyperinflammation and immunosuppression. Sepsis is highly correlated with the dysregulation of immune response, which is mainly mediated by various immune cells and their interactions. This syndrome can lead to a plethora of complications, encompassing systemic inflammatory response, metabolic disturbances, infectious shock, MODS, and DIC. Furthermore, more research studies have been conducted on sepsis in the past few years. The pathological characteristics of sepsis have been improved or treated by targeting signaling pathways like NF-B, JAK-STAT, PI3K-Akt, and p38-MAPK. Combined drug therapy is better than single drug therapy for sepsis. This article will review the latest progress in the pathogenesis and treatment of sepsis.

Keywords: Sepsis; T cells; cytokines; molecular mechanism; neutrophils.

Figure 1

Role of Neutrophils in Sepsis. When microorganisms or their products enter the bloodstream, they stimulate the bone marrow to release neutrophils, causing an increase in neutrophils in peripheral blood. LPS and C5a can activate the ERK1/2 and PI3K-AKT pathways to inhibit neutrophil apoptosis. LPS can also inhibit MNDA cleavage, leading to upregulation of Mcl-1 to suppress neutrophil apoptosis. Furthermore, C5a can upregulate Bcl-xL to suppress Bim expression, thereby inhibiting neutrophil apoptosis. The heightened liberation of neutrophils and reduced apoptosis enable them to more effectively combat pathogens by generating neutrophil extracellular traps (NETs) and releasing cytokines. However, when neutrophils are excessively activated, it may lead to severe consequences such as MODS, DIC, and immune suppression.

Figure 2

Role of T Cells in Sepsis. Upon microbial invasion, antigen-presenting cells activate T cells, leading to cellular immune reaction. TH1 cells enhance phagocytic activity and bactericidal capacity of macrophages, promote inflammatory reactions, and cellular immune responses by producing cytokines like IFN-γ and TNF-α. CD8+ T cells can recognize and eliminate the infected cells. CD4+ and CD25+ regulatory T cells can inhibit inflammatory response and prevent immune system from damage to their own tissues. However, when T cells are excessively activated, it can activate anti-inflammatory mechanisms, leading to immune suppression and T cell exhaustion. T cell exhaustion is predominantly linked to the excessive expression of inhibitory co-stimulatory receptors on the cell membrane, an upsurge in the proportion of Tregs, activation of the hypothalamic–pituitary–adrenal axis and sympathetic nervous system, heightened expression of calcium-sensitive receptors, and diminished levels of IL-7.

Figure 3

Immune cell response following bacterial infection. Neutrophils and macrophages are activated after bacterial infection. Neutrophils regulate T cells by releasing IL-2, IL-4, and promote inflammation by releasing TNF-α, IL-1β. Macrophages engulf pathogens through phagocytosis and present them to T cells via the MHC II pathway, promoting the differentiation of TH0 to TH1. TH1 cells activate CTL by secreting IL-2 and promote antibody production by plasma cells through the secretion of IF-γ, neutralizing extracellular toxins. Source from: Figdraw.

Figure 4

Ferroptosis in sepsis. In the pathogenesis of sepsis, abnormalities in iron metabolism, lipid peroxidation, dysregulation of the redox system, and decreased ferritin levels may lead to cellular metabolic disturbances. This disruption further triggers phospholipid peroxidation, resulting in ferroptosis of cells, ultimately culminating in organ dysfunction. Source from: Figdraw.