Aims Sepsis-associated encephalopathy (SAE) is a common complication of severe sepsis. Our goal was to investigate the role of immunity-related GTPase M1 (IRGM1) in SAE and its underlying mechanism. Methods A mouse sepsis model was established by cecal ligation and perforation. SAE was diagnosed by behavior, electroencephalography, and somatosensory evoked potentials. Wild-type mice with SAE were treated with SB203580 to block the p38 mitogen-activated protein kinase (MAPK) signaling pathway. We assessed hippocampal histological changes and the expression of IRGM1, interferon-γ (IFN-γ), and p38 MAPK signaling pathway-related proteins. Results Immunity-related GTPase M1 and IFN-γ levels increased in the hippocampus, with apoptosis, autophagy, and the p38 MAPK signaling pathway activated in neurons. Administration of SB203580 to mice with SAE reduced apoptosis and autophagy. Relative to wild-type mice with SAE, the general condition of Irgm1-/- mice with SAE was worsened, the p38 MAPK signaling pathway was inhibited, and neuronal apoptosis and autophagy were reduced. The absence of IRGM1 exacerbated SAE, with higher p38 MAPK signaling pathway activity and increased apoptosis and autophagy. Conclusions During SAE, IRGM1 can at least partially regulate apoptosis and autophagy in hippocampal neurons through the p38 MAPK signaling pathway.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cns.13229

Regulation of hippocampal neuronal apoptosis and autophagy in mice with sepsis-associated encephalopathy by immunity-related GTPase M1.

In the ongoing coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), natural killer T (NKT) cells act as primary initiators of immune responses. However, a decrease of circulating NKT cells has been observed in COVID-19 different stages, of which the underlying mechanism remains to be elucidated. Here, by performing single-cell RNA sequencing analysis in three large cohorts of COVID-19 patients, we found that increased expression of Tim-3 promotes depletion of NKT cells during the progression stage of COVID-19, which is associated with disease severity and outcome of patients with COVID-19. Tim-3+ NKT cells also expressed high levels of CD147 and CD26, which are potential SARS-CoV-2 spike binding receptors. In the study, Tim-3+ NKT cells showed high enrichment of apoptosis, higher expression levels of mitochondrial genes and caspase genes, with a larger pseudo time value. In addition, Tim-3+ NKT cells in COVID-19 presented a stronger capacity to secrete IFN-γ, IL-4 and IL-10 compared with healthy individuals, they also demonstrated high expression of co-inhibitory receptors such as PD-1, CTLA-4, and LAG-3. Moreover, we found that IL-12 secreted by dendritic cells (DCs) was positively correlated with up-regulated expression of Tim-3 in NKT cells in COVID-19 patients. Overall, this study describes a novel mechanism by which up-regulated Tim-3 expression induced the depletion and dysfunction of NKT cells in COVID-19 patients. These findings not only have possible implications for the prediction of severity and prognosis in COVID-19 but also provide a link between NKT cells and future new therapeutic strategies in SARS-CoV-2 infection.

https://www.frontiersin.org/articles/10.3389/fimmu.2022.796682/pdf

Increased Expression of Tim-3 Is Associated With Depletion of NKT Cells In SARS-CoV-2 Infection

Immune checkpoint molecule Tim-3 promotes NKT cell apoptosis and predicts poorer prognosis in Sepsis.

Background: Shock after traumatic injury is likely to be hypovolemic, but different types of shock (distributive shock, obstructive shock, or cardiogenic shock) can occur in combination, known as multifactorial shock. Multifactorial shock is a neglected area of study, and is only reported sporadically. Little is known about the incidence, characteristics, and outcomes of multifactorial shock after polytrauma. Methods: A retrospective, observational, multicenter study was conducted in four Level I trauma centers involving 1051 polytrauma patients from June 2020 to April 2022. Results: The mean Injury Severity Score (ISS) was 31.1, indicating a severely injured population. The most common type of shock in the early phase after polytrauma (≤48 h) is hypovolemic shock (83.2%), followed by distributive shock (14.4%), obstructive shock (8.7%), and cardiogenic shock (3.8%). In the middle phase after polytrauma (>48 h or ≤14 days), the most common type of shock is distributive shock (70.7%), followed by hypovolemic shock (27.2%), obstructive shock (9.9%), and cardiogenic shock (7.2%). Multifactorial shock accounted for 9.7% of the entire shock population in the early phase and 15.2% in the middle phase. In total, seven combinations of multifactorial shock were described. Patients with multifactorial shock have a significantly higher complication rate and mortality than those with single-factor shock. Conclusions: This study characterizes the incidence of various types of shock in different phases after polytrauma and emphasizes that different types of shock can occur simultaneously or sequentially in polytrauma patients. Multifactorial shock has a relatively high incidence and mortality in polytrauma patients, and trauma specialists should be alert to the possibility of their occurrence.

/pdf/multifactorial-shock-a-neglected-situation-in-polytrauma-2vec03n9.pdf

Multifactorial Shock: A Neglected Situation in Polytrauma Patients

Sepsis remains a significant cause of mortality and morbidity worldwide, with limited effective treatment options. The T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) has emerged as a potential therapeutic target in various immune-related disorders. This narrative review aims to explore the role of TIM-3 in sepsis and evaluate its potential as a promising target for immunotherapy. We discuss the dynamic expression patterns of TIM-3 during sepsis and its involvement in regulating immune responses. Furthermore, we examine the preclinical studies investigating the regulation of TIM-3 signaling pathways in septic models, highlighting the potential therapeutic benefits and challenges associated with targeting TIM-3. Overall, this review emphasizes the importance of TIM-3 in sepsis pathogenesis and underscores the promising prospects of TIM-3-based immunotherapy as a potential strategy to combat this life-threatening condition.

The role of TIM-3 in sepsis: a promising target for immunotherapy?

Alpha-lactose reverses liver injury via blockade of Tim-3-mediated CD8 apoptosis in sepsis

This study aimed to determine the therapeutic effectiveness of tuberculous aortic aneurysms (TBAAs) and the risk factors for mortality.We reviewed all case reports of TBAAs treated with open surgery or endovascular aneurysm repair (EVAR) from online database in 1996-2021. Only thoracic and abdominal aortic aneurysms were included.Eighty cases of open surgery and 42 cases of EVAR were included. The 2-year mortality and perioperative mortality rates of open surgery were 11.3% and 10.0%, respectively. Emergent open surgery had a significantly higher mortality (25.0%) than non-emergent open surgery (6.7%). In the EVAR group, 2-year mortality, perioperative mortality, and TBAA-related mortality were 16.7%, 4.8%, and 10.0%, respectively. Patients with typical tuberculosis (TB) symptoms before EVAR had a significantly higher TBAA-related mortality (35.0%) than patients with no typical TB symptoms before EVAR (0%). In the open surgery group, the rate of TB recurrence (2.7% vs 2.4%) and aneurysm recurrence (8.1% vs 7.3%) were quite close between preoperative anti-TB-treated and postoperative anti-TB-treated cases. However, in the EVAR group, TB recurrence (8.7% vs 0%) and aneurysm recurrence (12.5% vs 6.25%) were more common in postoperative anti-TB-treated cases.Open surgery was accompanied by higher perioperative mortality, whereas EVAR was followed with higher TBAA-related mortality. Emergent surgical choices of open surgery may be associated with high perioperative mortality. Typical TB symptoms before EVAR are a significant risk factor for mortality after EVAR. Early anti-TB treatment should be administered if EVAR is the surgical option. 

/pdf/therapeutic-effectiveness-of-tuberculous-aneurysm-and-risk-h2ynqlyn.pdf

Therapeutic effectiveness of tuberculous aneurysm and risk factors for mortality: a systematic review

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Alpha-lactose reverses liver injury via blockade of Tim-3-mediated CD8 apoptosis in sepsis

Therapeutic effectiveness of tuberculous aneurysm and risk factors for mortality: a systematic review