LILRA1 - leukocyte immunoglobulin like receptor A1 |Elisa - Clia - Antibody - Protein

Background

Leukocyte Immunoglobulin-Like Receptor A1 (LILRA1), also known as CD85i, is a member of the leukocyte immunoglobulin-like receptor (LILR) family, specifically the activating receptors. LILRs are primarily expressed on immune cells and contribute to immune response regulation. The LILR gene family is located on chromosome 19q13.4 and includes both activating (LILRA) and inhibitory (LILRB) receptors, which together modulate immune responses to maintain a balance between activating and inhibitory signals.

LILRA1 is an activating receptor and is most abundantly expressed on myeloid cells, including monocytes, macrophages, and certain dendritic cells. The receptor is also present on neutrophils and some lymphocyte populations. It is known to play a role in recognizing various ligands, including MHC class I molecules, although the exact ligand specificity of LILRA1 remains incompletely defined. The interaction between LILRA1 and its ligands triggers downstream signaling pathways, leading to enhanced immune responses, such as cytokine production and increased cell activation. Because of its role in immune activation, LILRA1 has been implicated in a variety of physiological and pathological processes, including infection, inflammation, and autoimmune diseases.

Protein Structure

LILRA1 possesses a structure typical of immunoglobulin-like receptors but with specific features that facilitate its activating functions. Key aspects of LILRA1’s structure include:

Extracellular Region:

• The extracellular region of LILRA1 contains two Ig-like domains, characteristic of the LILR family. Each domain is made up of approximately 90–110 amino acids and adopts a beta-sheet structure, stabilized by disulfide bridges. The first Ig-like domain is likely responsible for ligand binding, providing specificity for interactions with MHC class I molecules or other yet unidentified ligands.
• The domains form the interface through which LILRA1 recognizes and binds its ligands. This interaction is essential for activating the receptor and subsequent downstream signaling pathways.

Transmembrane Domain:

• LILRA1 is a single-pass transmembrane protein, with a hydrophobic transmembrane segment anchoring it to the cell membrane. This domain is essential for stabilizing LILRA1 on the cell surface and allowing interactions with other membrane-associated proteins, particularly signaling adaptors.
• The transmembrane domain lacks intrinsic signaling motifs, relying instead on association with signaling adaptors containing ITAMs for signal transduction.

Cytoplasmic Tail:

• The cytoplasmic tail of LILRA1 is short and lacks intrinsic signaling motifs like ITIMs. Instead, it interacts with ITAM-containing adaptor proteins, such as FcRγ, which initiate downstream signaling cascades upon ligand binding.
• The receptor’s ability to recruit ITAM-bearing adaptor molecules differentiates it from inhibitory LILRB receptors, which contain ITIMs in their cytoplasmic regions. By coupling with ITAMs, LILRA1 can transduce activation signals, leading to immune cell activation and pro-inflammatory cytokine production.

Classification and Subtypes

LILRA1 is part of the LILR family, which is subdivided into activating (LILRA) and inhibitory (LILRB) receptors based on their structural and functional characteristics. Members of the LILR family are primarily expressed on immune cells and help regulate immune responses by recognizing MHC class I molecules and other ligands. The activating LILRs (LILRA1, LILRA2, LILRA3, LILRA4) associate with ITAM-bearing adaptors, whereas inhibitory LILRs (LILRB1, LILRB2, LILRB3) contain ITIMs in their cytoplasmic domains and modulate immune responses through inhibitory signaling.

LILRA1 has no known subtypes and is expressed as a single gene product. However, its expression levels vary across different immune cell types and can be influenced by factors such as cell activation state and the presence of inflammatory stimuli.

Function and Biological Significance

LILRA1 functions as an activating receptor on immune cells, primarily myeloid cells. Upon engagement with ligands, LILRA1 associates with FcRγ to initiate downstream signaling, leading to immune cell activation and the promotion of inflammatory responses. The main functional roles of LILRA1 include:

Immune Cell Activation:

• LILRA1’s expression on monocytes, macrophages, and other myeloid cells allows it to play a pivotal role in immune activation. Ligand binding triggers the ITAM signaling pathway, resulting in cellular activation, increased phagocytic activity, and the release of inflammatory cytokines.
• This receptor's activation contributes to the innate immune response, enhancing the ability of myeloid cells to recognize and respond to pathogens.

Promotion of Cytokine Production:

• LILRA1 activation leads to the release of pro-inflammatory cytokines such as IL-1β, TNF-α, and IL-6, which are essential in the early stages of infection and inflammation. These cytokines help recruit immune cells to sites of infection or injury and promote inflammation.
• The release of cytokines also helps shape adaptive immunity by influencing the activation and differentiation of T cells.

Role in Host Defense:

• LILRA1’s activating role makes it essential in host defense, particularly against bacterial and viral infections. The receptor’s presence on macrophages and neutrophils enhances phagocytic activity, facilitating pathogen clearance.
• Some studies suggest that LILRA1 may play a role in the immune response to viruses by promoting antiviral cytokine production and enhancing the activity of natural killer (NK) cells.

Modulation of Monocyte and Macrophage Functions:

• LILRA1 regulates monocyte and macrophage activity by promoting cell differentiation and enhancing phagocytosis. These functions are critical in both innate immunity and the development of adaptive immune responses.

Clinical Issues

Autoimmune Diseases:

• Dysregulation of LILRA1 has been linked to autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Overexpression or hyperactivation of LILRA1 can lead to excessive cytokine production and inflammation, contributing to tissue damage in autoimmune conditions.

Chronic Inflammatory Diseases:

• Chronic activation of LILRA1 is associated with diseases characterized by persistent inflammation, including inflammatory bowel disease (IBD) and atherosclerosis. In these conditions, continuous LILRA1 activation may exacerbate inflammatory responses, leading to tissue damage.

Cancer:

• In the tumor microenvironment, LILRA1 may play a dual role. On one hand, it could promote anti-tumor immunity by activating immune cells, while on the other hand, chronic LILRA1 activation could potentially lead to immune exhaustion, impairing anti-tumor responses. The precise role of LILRA1 in cancer immunity is still under investigation, but it represents a potential target for immunotherapy.

Infectious Diseases:

• The role of LILRA1 in host defense makes it relevant in infectious diseases, especially in cases where an enhanced immune response is beneficial. However, in chronic infections like HIV or hepatitis B, persistent activation of LILRA1 could contribute to immune exhaustion, reducing the ability to control infection over time.

Therapeutic Targeting:

• LILRA1 is a potential therapeutic target for modulating immune responses. In autoimmune diseases, inhibiting LILRA1 could reduce inflammation and cytokine production, alleviating symptoms. Conversely, in immunosuppressive conditions or infections, activating LILRA1 could enhance immune responses.

Summary

LILRA1, a member of the leukocyte immunoglobulin-like receptor family, is an activating receptor expressed on myeloid cells such as monocytes, macrophages, and certain granulocytes. The receptor plays a critical role in immune cell activation, promoting cytokine production, and enhancing phagocytic activity, thus contributing to the body’s defense against infections. Structurally, LILRA1 consists of two extracellular Ig-like domains, a single-pass transmembrane domain, and a short cytoplasmic tail that associates with ITAM-bearing adaptor proteins for signal transduction.

LILRA1’s role in immune activation makes it significant in various physiological and pathological contexts. It is implicated in autoimmune diseases, chronic inflammatory conditions, infectious diseases, and possibly cancer. Therapeutically, LILRA1 could be targeted to either enhance or inhibit immune responses, depending on the disease context.