positive regulation of leukocyte tethering or rolling

Definition

Target type: biologicalprocess

Any process that activates or increases the frequency, rate or extent of leukocyte tethering or rolling. [GO_REF:0000058, GOC:als, GOC:TermGenie, PMID:18308860]

Leukocyte tethering and rolling is a crucial initial step in the recruitment of leukocytes (white blood cells) to sites of inflammation and infection. This process is tightly regulated to ensure the efficient and controlled delivery of immune cells to areas of need. Positive regulation of leukocyte tethering and rolling involves a complex interplay of molecular interactions between leukocytes and the vascular endothelium, the inner lining of blood vessels.

1. **Selectins:** Initiating the process are selectins, a family of adhesion molecules expressed on both leukocytes and endothelial cells. Specifically, P-selectin and E-selectin are rapidly expressed on endothelial cells in response to inflammatory stimuli. L-selectin is constitutively expressed on leukocytes. The selectins bind to carbohydrate ligands displayed on the surface of leukocytes (e.g., PSGL-1) and endothelial cells (e.g., GlyCAM-1, CD34). These interactions are relatively weak but crucial for the initial capture and rolling of leukocytes along the endothelium.

2. **Chemokines:** Leukocyte rolling is further influenced by chemokines, small signaling molecules that attract leukocytes towards sites of inflammation. Chemokines are released by activated endothelial cells and other cells at the site of inflammation. They bind to specific receptors on leukocytes, triggering a conformational change in the selectin ligands, strengthening the interaction between leukocytes and the endothelium. This leads to a slower rolling velocity and an increased probability of firm adhesion.

3. **Integrins:** Firm adhesion is mediated by integrins, a family of transmembrane receptors that are expressed on leukocytes. Integrins are typically in an inactive state but become activated by chemokine signaling. They bind to their respective ligands on endothelial cells, such as ICAM-1 and VCAM-1. This strong binding effectively anchors the leukocyte to the endothelium.

4. **Inside-Out Signaling:** Inside-out signaling refers to the process by which chemokines activate intracellular signaling pathways within leukocytes, leading to changes in integrin conformation and affinity for their ligands. This process is critical for the transition from weak tethering and rolling to firm adhesion.

5. **Outside-In Signaling:** Outside-in signaling refers to the signals initiated by the binding of integrins to their ligands on the endothelium. These signals contribute to cytoskeletal reorganization within the leukocyte, ultimately leading to the formation of a firm adhesive bond between the leukocyte and the endothelium.

6. **Diapedesis:** After firm adhesion, leukocytes undergo diapedesis, a process by which they migrate across the endothelial barrier and into the tissues. This involves further molecular interactions and signaling pathways.

Positive regulation of leukocyte tethering and rolling is essential for the proper functioning of the immune system. A well-regulated process ensures that leukocytes are efficiently recruited to sites of inflammation and infection, allowing them to effectively combat pathogens and promote tissue repair. Dysregulation of this process can lead to a variety of inflammatory and autoimmune disorders.'
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Proteins (7)

Compounds (161)