Endoplasmic Reticulum Homeostasis Regulates TLR4 Expression and Signaling in Mast Cells

Abstract

The endoplasmic reticulum (ER) is a dynamic organelle that responds to demand in secretory proteins by undergoing expansion. The mechanisms that control the homeostasis of ER size and function involve the activation of the unfolded protein response (UPR). The UPR plays a role in various effector functions of immune cells. Mast cells (MCs) are highly granular tissue-resident cells and key drivers of allergic inflammation. Their diverse secretory functions in response to activation through the high-affinity receptor for IgE (FcεRI) suggest a role for the UPR in their function. Using human cord blood-derived MCs, we found that FcεRI triggering elevated the expression level and induced activation of the UPR transducers IRE1α and PERK, accompanied by expansion of the ER. In mouse bone marrow-derived MCs and peritoneal MCs, the ER underwent a more moderate expansion, and the UPR was not induced following MC activation. The deletion of IRE1α in mouse MCs did not affect proliferation, survival, degranulation, or cytokine stimulation following FcεRI triggering, but it did diminish the surface expression of TLR4 and the consequent response to LPS. A similar phenotype was observed in human MCs using an IRE1α inhibitor. Our data indicate that the ER of MCs, primarily of humans, undergoes a rapid remodeling in response to activation that promotes responses to TLR4. We suggest that IRE1α inhibition can be a strategy for inhibiting the hyperactivation of MCs by LPS over the course of allergic responses.

Inhibition of Hepatocellular Carcinoma by Endogenous Lipids: Induction of Pyroptosis by Geranylgeranoic Acid—A Comparison with Palmitic Acid and Retinoic Acid

“…One involves the UPR ER , detected as the splicing of XBP1 mRNA and upregulation of DDIT3 mRNA, along with the consequent activation of ER-resident CASP4, leading to the formation of GSDMD pores through the cleavage of GSDMD by active CASP4 and the translocation of the GSDMD N-terminal fragment to the cell membrane (Figure 1, left). Although the precise mechanism linking TLR4 signaling to UPR ER is not yet clear, several reports suggest that stimulation of TLR4 induces UPR ER , particularly the splicing of XBP1 mRNA [20][21][22][23].…”

Induction of Hepatoma Cell Pyroptosis by Endogenous Lipid Geranylgeranoic Acid—A Comparison with Palmitic Acid and Retinoic Acid

“…One involves the UPR ER , detected as the splicing of XBP1 mRNA and upregulation of DDIT3 mRNA, along with the consequent activation of ER resident CASP4, leading to the formation of GSDMD pores through the cleavage of GSDMD by active CASP4 and the translocation of the GSDMD N-terminal fragment to the cell membrane (Figure 2, left). Although the precise mechanism linking TLR4 signaling to UPR ER is not yet clear, several reports suggest that the stimulation of TLR4 induces UPR ER , particularly the splicing of XBP1 mRNA [22][23][24][25].…”

4-Phenylbutyric Acid Attenuates Soybean Glycinin/β-Conglycinin-Induced IPEC-J2 Cells Apoptosis by Regulating the Mitochondria-Associated Endoplasmic Reticulum Membrane and NLRP-3

“…Studies have shown that the intestine is the main site of damage caused by soybean antigenic protein in weaned piglets, which is manifested by shortened retention time of chyme, disturbed nutrient and mineral transport and absorption, intestinal villi atrophy, and impaired small intestinal barrier structure, which leads to diarrhea, growth inhibition, and even death. 6,7 However, maintenance of the intestinal barrier is closely linked to intestinal epithelial cell (IEC) homeostasis [integrity of tight junctions (TJs), immune responses, programmed cell death, and proliferation]. 8 IECs, which constitute barrier and messenger cells between the intestinal luminal and the host immune system, are highly susceptible to endoplasmic reticulum (ER) stress (ERS).…”

“…Animal growth performance correlates positively with intestinal barrier function, suggesting that an intact intestinal barrier is a key determinant of animal health and growth performance. Studies have shown that the intestine is the main site of damage caused by soybean antigenic protein in weaned piglets, which is manifested by shortened retention time of chyme, disturbed nutrient and mineral transport and absorption, intestinal villi atrophy, and impaired small intestinal barrier structure, which leads to diarrhea, growth inhibition, and even death. , …”