I would like to warmly invite you to our next Nencki Institute Seminar on the 16th of November at 3pm in the CN lecture hall. We will host Dr. Anna Ciesielska. Dr. Ciesielska's lecture will be entitled: "Membrane proteins and lipids as regulators of bacterial lipopolysaccharide-induced inflammatory responses of macrophages"
When innate immune cells, like macrophages, detect lipopolysaccharide (LPS) derived from Gram-negative bacteria, they trigger an inflammatory response to combat the invading pathogens. A key component of this process is the LPS receptor, Toll-like receptor (TLR) 4 present in the plasma membrane of macrophages. TLR4 initiates signaling pathways leading to the production of inflammatory mediators (including cytokines) that subsequently activate other immune and non-immune cells. While a rapid and effective activation of TLR4 is essential for the eradication of pathogens, an excessive inflammatory response can lead to severe, potentially fatal sepsis. Moreover, prolonged low-grade inflammation contributes to the development of civilization diseases. Therefore, it is of particular interest to reveal molecular mechanisms modulating the signaling activity of TLR4, which, depending on the context, can enhance or alleviate the pro-inflammatory response of macrophages.
This lecture will summarize studies that allowed us to detect new points of regulation of the TLR4 signaling in macrophages. I will present the immunomodulatory potential of physiologically relevant lipids - lysophosphatidic acid, lysobisphosphatidic acid, and sphingolipids, which fine-tune the signaling pathways of TLR4 via interaction with specific receptors or by direct incorporation into cellular membranes. Next, I will focus on CD14, a GPI-anchored accessory protein of TLR4 located in sphingomyelin/cholesterol nanodomains of the plasma membrane (rafts) and crucial for activation of the receptor by LPS. We found that after endocytosis, CD14 undergoes recycling that facilitates the maintenance of optimal CD14 level in the plasma membrane. This process involves sorting nexins (SNX1, 2, 6) and its inhibition reduces the amount of CD14 on the cell surface, weakening the inflammatory response of macrophages to LPS. CD14 recycling is also controlled by flotillins, proteins associated with membrane rafts in a lipid-dependent manner. Taken together, the data indicate that lipids affect LPS-induced signaling acting as receptor ligands and modulators of cellular membrane organization or protein-membrane interactions.
The lecture will be followed by a get together.
With best wishes