ITGAD - integrin subunit alpha D |Elisa - Clia - Antibody - Protein

Background

ITGAD (integrin subunit alpha D), also known as CD11d, is a member of the integrin family of cell adhesion molecules. Integrins are heterodimeric receptors consisting of an alpha and a beta subunit, which mediate cell-cell and cell-extracellular matrix interactions. ITGAD pairs with the beta-2 integrin subunit (CD18) to form the αDβ2 (CD11d/CD18) integrin. This integrin is predominantly expressed on myeloid cells, including macrophages, dendritic cells, monocytes, and natural killer (NK) cells, as well as certain subpopulations of lymphocytes. ITGAD, as part of the β2 integrin subfamily, plays a critical role in immune responses, particularly in cell adhesion, migration, and phagocytosis.

ITGAD is the least well-characterized among the beta-2 integrins, but emerging research has highlighted its significance in specialized immune responses, such as the clearance of apoptotic cells, regulation of inflammation, and leukocyte recruitment to chronic inflammatory sites. Additionally, ITGAD has been implicated in processes such as tissue remodeling and wound healing. Due to its involvement in these crucial immune processes, ITGAD has garnered increasing attention in the study of immune system regulation and pathologies, including chronic inflammation, autoimmune diseases, and cancer.

Protein Structure

The ITGAD protein (CD11d) is a large transmembrane glycoprotein with approximately 1,150 amino acids. Like other integrins, its structure consists of several distinct domains, each contributing to its functions in ligand binding, cell adhesion, and signaling.

Extracellular Domain:

• The extracellular region of ITGAD comprises most of the protein (~1,100 amino acids) and is responsible for ligand binding. Similar to other integrins in the beta-2 subfamily, the extracellular region is made up of several functional subdomains:
• I (inserted) domain: The I domain is one of the most critical regions for ligand binding in ITGAD. It adopts a Rossmann fold and includes the metal ion-dependent adhesion site (MIDAS), which coordinates divalent cations (typically Mg²⁺ or Mn²⁺). These cations are essential for stabilizing the interaction between ITGAD and its ligands, such as ICAM-3 (intercellular adhesion molecule 3), VCAM-1 (vascular cell adhesion molecule 1), and other extracellular matrix components. The I domain is crucial for mediating interactions between immune cells and their targets during immune responses.
• Beta-propeller domain: This domain is located in the N-terminal portion of the extracellular region and features a seven-bladed beta-sheet structure. The beta-propeller domain contributes to ligand specificity and interacts with the beta-2 subunit (CD18) to modulate ligand binding and signaling.
• Thigh and calf domains (calf-1 and calf-2): These membrane-proximal regions contribute to the structural integrity and flexibility of the extracellular region. The thigh and calf domains undergo conformational changes that are necessary for switching ITGAD between inactive and active states, allowing for high-affinity ligand binding during immune activation.

Transmembrane Domain:

• The transmembrane domain of ITGAD is composed of a single alpha-helix that anchors the protein within the cell membrane. This domain is essential for integrin heterodimerization, where ITGAD non-covalently associates with the beta-2 subunit (CD18) to form the functional αDβ2 integrin. Additionally, the transmembrane domain is involved in transducing signals from outside the cell into the cytoplasm, thereby influencing cellular responses.

Cytoplasmic Tail:

• The cytoplasmic tail of ITGAD is relatively short (~20-30 amino acids), yet it plays a pivotal role in signal transduction. It interacts with cytoskeletal proteins and intracellular signaling molecules, regulating processes such as cell adhesion, migration, and phagocytosis. The cytoplasmic domain is involved in both inside-out signaling, where intracellular signals modulate the integrin’s affinity for ligands, and outside-in signaling, where extracellular ligand binding triggers intracellular signaling pathways.

Classification and Subtypes

ITGAD belongs to the integrin family, a large group of cell adhesion receptors that consist of alpha and beta subunit heterodimers. ITGAD pairs with CD18 (beta-2 integrin subunit) to form the αDβ2 integrin. The beta-2 integrin subfamily includes four major members, all of which are primarily expressed on leukocytes (white blood cells) and are involved in immune responses:

1. LFA-1 (αLβ2, CD11a/CD18): Critical for leukocyte adhesion, T-cell activation, and immune synapse formation.
2. Mac-1 (αMβ2, CD11b/CD18): Plays a key role in phagocytosis, neutrophil migration, and complement receptor activity.
3. p150,95 (αXβ2, CD11c/CD18): Involved in phagocytosis, antigen presentation, and immune cell adhesion.
4. αDβ2 (CD11d/CD18): The focus of this review, αDβ2 is primarily involved in immune cell adhesion to the extracellular matrix, clearance of apoptotic cells, and chronic inflammation regulation.

The αDβ2 integrin is somewhat unique among its counterparts due to its expression profile and its role in specific immune contexts, such as in chronic inflammatory sites and certain lymphoid tissues.

Function and Biological Significance

ITGAD, as part of the αDβ2 (CD11d/CD18) integrin, performs several critical immune functions, most notably in cell adhesion, immune cell migration, and phagocytosis. Some of its key roles include:

1. Immune Cell Adhesion and Migration: ITGAD facilitates adhesion of leukocytes to components of the extracellular matrix, such as VCAM-1 and ICAM-3, particularly at sites of chronic inflammation. This adhesion is critical for immune cells to migrate from the bloodstream into tissues where they are needed for immune surveillance, tissue repair, or to combat infection. ITGAD is also involved in immune cell retention at sites of inflammation, helping maintain the presence of macrophages and dendritic cells in affected tissues.
2. Phagocytosis and Clearance of Apoptotic Cells: ITGAD plays a role in phagocytosis, particularly the clearance of apoptotic cells (efferocytosis). This is important for maintaining tissue homeostasis and preventing chronic inflammation or autoimmunity. By binding to ligands on apoptotic cells, ITGAD facilitates their recognition and engulfment by phagocytic cells, such as macrophages, helping to resolve inflammation and promote tissue repair.
3. Regulation of Chronic Inflammation: ITGAD is highly expressed in tissues that are subjected to chronic inflammatory stimuli, such as atherosclerotic lesions and fibrotic tissues. It mediates the recruitment and retention of macrophages at these sites, where they contribute to tissue remodeling and fibrosis. Additionally, ITGAD helps regulate the balance between pro-inflammatory and anti-inflammatory signals, potentially influencing the resolution of chronic inflammation or its progression to fibrosis or tissue damage.
4. Tissue Repair and Remodeling: ITGAD is involved in processes related to wound healing and tissue remodeling, particularly in chronic inflammation. By facilitating the interaction of immune cells with the extracellular matrix, ITGAD contributes to the structural reorganization of tissues and the repair of damaged areas. This is especially relevant in diseases involving tissue fibrosis or excessive scarring.
5. Immune Surveillance: ITGAD, through its interaction with ICAMs and other adhesion molecules, plays a role in immune surveillance, particularly in lymphoid tissues. Dendritic cells and macrophages that express ITGAD help monitor for pathogens, damaged cells, or other immune triggers, facilitating rapid immune responses.

Clinical Issues

Given its role in immune regulation, ITGAD has been implicated in several clinical conditions, particularly those related to chronic inflammation and autoimmune diseases.

1. Atherosclerosis and Cardiovascular Disease: ITGAD is highly expressed in atherosclerotic plaques, where it contributes to the recruitment and retention of macrophages. These macrophages can become foam cells, exacerbating plaque formation and instability, which are central features of atherosclerosis. Elevated expression of ITGAD in atherosclerotic lesions has been associated with the progression of cardiovascular disease, making it a potential therapeutic target for treating or preventing atherosclerosis.
2. Fibrosis and Chronic Inflammatory Diseases: In conditions such as pulmonary fibrosis, liver cirrhosis, and chronic obstructive pulmonary disease (COPD), ITGAD-mediated interactions between immune cells and the extracellular matrix contribute to the persistent inflammation and tissue remodeling that characterize these diseases. Targeting ITGAD may help reduce immune cell infiltration and fibrosis in these conditions, potentially improving outcomes for patients.
3. Autoimmune Diseases: Abnormal expression or function of ITGAD has been implicated in certain autoimmune diseases, where dysregulated immune responses lead to chronic inflammation and tissue damage. Although ITGAD’s precise role in autoimmune diseases remains under investigation, it is thought to contribute to the recruitment and activation of immune cells in affected tissues.
4. Cancer: ITGAD has been studied in the context of tumor immunity, particularly its role in immune cell infiltration into tumors. While immune cells such as macrophages can sometimes help eliminate cancer cells, in other cases, tumor-associated macrophages expressing ITGAD may promote tumor growth by facilitating immune evasion or supporting the tumor microenvironment.
5. Therapeutic Targeting: Given its involvement in chronic inflammation and tissue remodeling, ITGAD represents a potential therapeutic target for a variety of diseases. Inhibiting αDβ2 integrin could be useful in reducing immune cell recruitment to sites of chronic inflammation, thereby mitigating the progression of diseases such as atherosclerosis, fibrosis, and certain autoimmune conditions.

Summary

ITGAD (integrin subunit alpha D, CD11d) is a crucial component of the immune system, particularly within the context of chronic inflammation, immune cell migration, and tissue remodeling. As part of the αDβ2 integrin, ITGAD mediates cell adhesion, immune cell retention, and the clearance of apoptotic cells. Structurally, ITGAD features an extracellular domain with a ligand-binding I domain and a transmembrane domain that facilitates its dimerization with CD18. ITGAD's functions are critical for the regulation of chronic inflammation, tissue repair, and immune surveillance. Its dysregulation has been implicated in conditions such as atherosclerosis, fibrosis, autoimmune diseases, and cancer, making it a promising target for therapeutic intervention.