The role of the globular heads of the C1q receptor in TcdA-induced human colonic epithelial cell apoptosis via a mitochondria-dependent pathway

Abstract

Background: Clostridioides (formerly Clostridium) difficile infection is the leading cause of antibiotic-associated colitis. Studies have demonstrated that C. difficile toxin A (TcdA) can cause apoptosis of many human cell types. The purpose of this study was to investigate the relationships among exposure to TcdA, the role of the receptor for the globular heads of C1q (gC1qR) gene and the underlying intracellular apoptotic mechanism in human colonic epithelial cells (NCM 460). In this study, gC1qR expression was examined using real-time polymerase chain reaction (PCR), western blotting and immunohistochemical staining. Cell viability was assessed by the water-soluble tetrazolium salt (WST-1) assay, and cell apoptosis was assessed by flow cytometry and the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) assay. Mitochondrial function was assessed based on reactive oxygen species (ROS) generation, changes in the mitochondrial membrane potential (ΔΨm) and the content of ATP. Results: Our study demonstrated that increasing the concentration of TcdA from 10 ng/ml to 20 ng/ml inhibited cell viability and induced cell apoptosis (p < 0.01). Moreover, the TcdA-induced gC1qR expression and enhanced expression of gC1qR caused mitochondrial dysfunction (including production of ROS and decreases in the ΔΨm and the content of ATP) and cell apoptosis. However, silencing of the gC1qR gene reversed TcdA-induced cell apoptosis and mitochondrial dysfunction. Conclusion: These data support a mechanism by which gC1qR plays a crucial role in TcdA-induced apoptosis of human colonic epithelial cells in a mitochondria-dependent manner.

Walnut-Derived Peptides Alleviate Learning and Memory Impairments in a Mice Model via Inhibition of Microglia Phagocytose Synapses

“…Some studies have shown that increased microglia activation results from the release of large amounts of C1q. , Reduced microglia activation in the AD mice model is associated with C1q loss . Following this, we assessed the effect of TW-7 on the activation of microglia by C1q in mice treated with LPS (Figure C).…”

Exploring the Toxin-Mediated Mechanisms in Clostridioides difficile Infection

“…TcdA may induce Bak protein production via prostaglandin E2 [136,137]. The death receptor pathway involves caspase 8 activation by the tumor necrosis factor-alpha (TNF-α) or Fas binding, triggering cell death and cytochrome c release from mitochondria [133,138].…”

“…Toxins weaken granule cohesion with the plasma membrane, facilitating degranulation via actin rearrangement. TcdB activates intracellular signaling in mast cells, including p38 MAP, promoting prostaglandin production and degranulation [138,173]. Interestingly, mast cell-deficient mice show reduced inflammatory responses and do not develop TcdA-induced enteritis [153].…”