negative regulation of leukocyte tethering or rolling

Definition

Target type: biologicalprocess

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

Negative regulation of leukocyte tethering or rolling is a crucial process in maintaining immune homeostasis and preventing excessive inflammation. It involves a complex interplay of molecular interactions between leukocytes and the vascular endothelium, ultimately controlling the adhesion and migration of leukocytes from the bloodstream into tissues.

**Key Steps Involved:**

1. **Initial Tethering and Rolling:** Leukocytes initially interact with the vascular endothelium through weak, transient interactions mediated by selectins. These interactions are facilitated by selectin ligands expressed on leukocytes, such as P-selectin glycoprotein ligand-1 (PSGL-1) and L-selectin ligand, and their corresponding selectins on endothelial cells (E-selectin, P-selectin, and L-selectin). This tethering and rolling allows for the initial capture of leukocytes and their slow rolling along the blood vessel wall, providing an opportunity for further activation and firm adhesion.

2. **Signal Transduction and Activation:** As leukocytes roll along the endothelium, they encounter chemokines, such as CXCL8 (IL-8), and other pro-inflammatory mediators that activate specific receptors on their surface. These receptors, such as chemokine receptors and integrins, trigger intracellular signaling pathways that lead to leukocyte activation and increased integrin affinity.

3. **Integrin Activation and Firm Adhesion:** Activated integrins on leukocytes, such as LFA-1 (lymphocyte function-associated antigen 1) and Mac-1 (Macrophage-1 antigen), bind to their counter-receptors, ICAM-1 (intercellular adhesion molecule-1) and ICAM-2 (intercellular adhesion molecule-2), expressed on endothelial cells. This interaction is much stronger than selectin-mediated tethering and rolling, resulting in firm adhesion of leukocytes to the endothelium.

4. **Transmigration:** Once firmly adhered, leukocytes can transmigrate through the endothelial barrier and enter the surrounding tissue, where they can perform their specific functions. This process involves complex interactions with other adhesion molecules and signaling pathways.

**Negative Regulation:**

Negative regulation of leukocyte tethering or rolling is essential to prevent uncontrolled inflammation and tissue damage. This process involves multiple mechanisms, including:

* **Downregulation of Selectin Expression:** Endothelial cells can decrease the expression of selectins (E-selectin, P-selectin, and L-selectin) on their surface, reducing the initial tethering and rolling of leukocytes.
* **Shedding of Selectin Ligands:** Leukocytes can shed their selectin ligands (PSGL-1 and L-selectin ligand) from their surface, further reducing their ability to interact with selectins on endothelial cells.
* **Inhibition of Integrin Activation:** Signals from anti-inflammatory mediators, such as IL-10 and TGF-β, can inhibit the activation of integrins on leukocytes, preventing their firm adhesion to the endothelium.
* **Expression of Inhibitory Molecules:** Endothelial cells can express inhibitory molecules, such as CD31 (platelet endothelial cell adhesion molecule 1) and JAM-A (junctional adhesion molecule A), which can interfere with leukocyte adhesion and transmigration.

**Consequences of Dysregulation:**

Dysregulation of leukocyte tethering or rolling can lead to chronic inflammation and various disease states. Excessive leukocyte recruitment can contribute to autoimmune diseases, inflammatory bowel disease, atherosclerosis, and other inflammatory conditions. Conversely, impaired leukocyte recruitment can compromise immune responses against pathogens and infections.

**Conclusion:**

Negative regulation of leukocyte tethering or rolling is a critical process that ensures the proper recruitment of leukocytes to sites of inflammation while preventing uncontrolled inflammation and tissue damage. This intricate regulatory system involves a complex network of molecular interactions and signaling pathways, and its disruption can contribute to a variety of inflammatory and autoimmune diseases.'
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Proteins (1)

Compounds (3)