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Review
. 2024 Aug 29:11:1429370.
doi: 10.3389/fmed.2024.1429370. eCollection 2024.

Molecular mechanisms of Sepsis attacking the immune system and solid organs

Zhaoyun Yang #  1   2 , Yan Gao #  3 , Lijing Zhao  2 , Xuejiao Lv  1 , Yanwei Du  2
Affiliations
Review

Molecular mechanisms of Sepsis attacking the immune system and solid organs

Zhaoyun Yang et al. Front Med (Lausanne). .

Abstract

Remarkable progress has been achieved in sepsis treatment in recent times, the mortality rate of sepsis has experienced a gradual decline as a result of the prompt administration of antibiotics, fluid resuscitation, and the implementation of various therapies aimed at supporting multiple organ functions. However, there is still significant mortality and room for improvement. The mortality rate for septic patients, 22.5%, is still unacceptably high, accounting for 19.7% of all global deaths. Therefore, it is crucial to thoroughly comprehend the pathogenesis of sepsis in order to enhance clinical diagnosis and treatment methods. Here, we summarized classic mechanisms of sepsis progression, activation of signal pathways, mitochondrial quality control, imbalance of pro-and anti- inflammation response, diseminated intravascular coagulation (DIC), cell death, presented the latest research findings for each mechanism and identify potential therapeutic targets within each mechanism.

Keywords: apoptosis; inflammation; mechanism; pathogenesis; pyroptosis; sepsis.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
The signaling pathways through which immune cells recognize microbes and mediate immune responses. Upon initiation of sepsis, innate immune cells become activated upon recognition of DAMPs and PAMPs. Receptors located on the cell membrane and within the cell detect these danger signals, initiating various pathways that modulate the activation and regulation of innate immune responses. Typically, these pathways converge toward the IRF3 and NF-κB signaling pathways, which are crucial for the onset of early-phase inflammatory responses. Moreover, the activation of TLR4 by agonists serves as a vital priming signal for the initial steps of inflammasome activation, involving the upregulation of pro-inflammatory genes. Another important group of pathogenic substances and endogenous alarm signals are necessary to provide the second signal for the assembly of AIM2/NLRP3 inflammasomes, triggering the cleavage of caspases, GSDMD, and pro-IL-1β/18, leading to the canonical activation of inflammasomes and pyroptosis. Intracellularly, cfDNA originating from apoptotic cells or intracellular pathogens can be sensed by AIM2 and cGAS-STING, promoting inflammasome assembly and the phosphorylation of IRF3, ultimately inducing type I interferon responses and inflammasome activation. DAMP damage-associated molecular pattern, PAMP pathogen-associated molecular pattern, cfDNA cell-free DNA, ASC apoptosis-associated speck-like protein, GSDMD gasdermin D. Created with BioRender.com.
Figure 2
Figure 2
Sepsis disrupts cellular mitochondrial quality control. As sepsis advances, mitophagy is hindered. Furthermore, heightened mitochondrial fission and decreased mitochondrial fussion are evidenced as a reaction to sepsis-induced stress. There is a noticeable decrease in mitochondrial biogenesis is observed. This decline is predominantly influenced by increased levels of the cytokine TNFα, resulting in reduced levels of PGC-1α. Created with BioRender.com.
Figure 3
Figure 3
Imbalance of immune homeostasis in sepsis: pro-inflammatory and anti-inflammation responses. Sepsis is characterized by the simultaneous interplay of pro- and anti-inflammatory mechanisms. The proinflammatory response involves the release of pro-inflammatory mediators, activation of the complement and coagulation systems, and the release of alarmins due to necrotic cell death. On the other hand, the anti-inflammatory response is marked by impaired immune cell function caused by effector cell apoptosis, T cell exhaustion, heightened expression of suppressor cells, and the inhibition of pro-inflammatory gene transcription. Created with BioRender.com.
Figure 4
Figure 4
Cell death modalities in sepsis. Mitochondria-generated ROS and mtDNA act as triggers for the activation of the JAK–STAT pathway and the suppression of HDAC1, necessary for the hyperacetylation and movement of HMBG1 to the cytosol. Upon exposure to pathogenic stimuli, a significant amount of thiol-reduced HMGB1 is released through exosomes, functioning as inflammatory agents in sepsis. This redox state of HMGB1 interacts with AIM2 to initiate inflammasome activation and caspase-1-mediated responses, which are essential for inducing apoptosis/pyroptosis. Created with BioRender.com.
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Grants and funding

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This work was supported by Natural Science Foundation General Program of Jilin Provincial Science and Technology Department (No. YDZJ202301ZYTS107 and (JKH20241356KJ), (JKH20231212KJ), (YDZJ202401270ZYTS), (20230304095YY), (20220508064RC)), National Natural Science Foundation of China (No. 81600207), National College Students’ innovation and entrepreneurship training program (Nos. 202210199006 and 202210199041).

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