Neuronal MD2 induces long-term mental impairments in septic mice by facilitating necroptosis and apoptosis

Abstract

Sepsis-associated encephalopathy (SAE) is a complication of sepsis with high morbidity rates. Long-lasting mental health issues in patients with SAE result in a substantial decrease in quality of life. However, its underlying mechanism is unclear, and effective treatments are not available. In the current study, we explored the role of apoptosis and necroptosis related to mental dysfunction in sepsis. In a mouse model of sepsis constructed by cecal ligation and puncture (CLP), altered behavior was detected by the open field, elevated-plus maze and forced swimming tests on the fourteenth day. Moreover, apoptosis- and necroptosis-associated proteins and morphological changes were examined in the hippocampus of septic mice. Long-lasting depression-like behaviors were detected in the CLP mice, as well as significant increases in neuronal apoptosis and necroptosis. Importantly, we found that apoptosis and necroptosis were related according to Ramsay’s rule in the brains of the septic mice. Inhibiting myeloid differentiation factor 2 (MD2), the crosstalk mediator of apoptosis and necroptosis, in neurons effectively reduced neuronal loss and alleviated depression-like behaviors in the septic mice. These results suggest that neuronal death in the hippocampus contributes to the mental impairments in SAE and that inhibiting neuronal MD2 is a new strategy for treating mental health issues in sepsis by inhibiting necroptosis and apoptosis.

Identification of featured necroptosis-related genes and imbalanced immune infiltration in sepsis via machine learning

“…A clinical study showed that the plasma level of HMGB1 was associated with RIPK3 and MLKL , and elevated HMGB1 ultimately led to poor prognosis in septic patients ( Chen et al, 2020 ; Yoo et al, 2021 ). Fan et al found that in the cecal ligation and puncture (CLP) septic mice model, down-regulating the expression of myeloid differentiation factor 2 (MD-2), which was the mediator of crosstalk between apoptosis and necroptosis in neurons, could reduce depressive-like behavior in sepsis-associated encephalopathy ( Fan et al, 2022 ). In the study, we found that 4 necroptosis-related hub genes ( BACH2, GATA3, LEF1, and BCL2 ) were closely related to sepsis, providing a potential new target for the diagnosis and therapy of sepsis.…”

Tat-CIRP Peptide Facilitates Frozen Wound Healing by Ameliorating Inflammation and Promoting Angiogenesis

“…Based on a previous study on the high affinity between CIRP and MD2, 14 , 17 , 18 we synthesized a peptide that mimics the CIRP 106–125 domain and linked it to the human immunodeficiency virus type 1 transcriptional activator TAT peptide (YGRKKRRQRRR) to form Tat-CIRP (YGRKKRRQRRR-GRGFSRGGGDRGYGG) for the next study.…”

“…[14][15][16] Tat-CIRP, as a peptide, penetrates into cells via the HIV Tat sequence and interferes with MD2 via the 15 aa sequence in CIRP. To date, several studies have proven the potential therapeutic applications of Tat-CIRP in various diseases, including stroke 17 and sepsis, 18 through inhibiting proinflammatory cytokines production and improving survival rates. However, whether Tat-CIRP peptide exerts its effects in frostbite treatment through the suppression of inflammation remains unclear.…”

Necroptosis in CNS diseases: Focus on astrocytes

“…Chronic depressive-like behavior, as well as a significant increase in neuronal apoptosis and necroptosis, were detected in mice with a sepsis model by cecal ligation and puncture (CLP). Inhibition of myeloid differentiation factor 2 (MD2), a mediator of both apoptosis and necroptosis, reduced neuronal death and improved depressive behavior in animals (Fan et al, 2022). Summing up, necroptosis and RIPK1 may also be a target for the correction of depressive disorders.…”