IL34 - interleukin 34 |Elisa - Clia - Antibody - Protein

Background

Interleukin 34 (IL-34) is a pro-inflammatory cytokine identified in 2008 through bioinformatics analysis of the human genome. Unlike most interleukins, which were discovered through their immunological properties, IL-34 was initially identified for its role as a ligand for the colony-stimulating factor-1 receptor (CSF1R), a receptor known to regulate the survival, proliferation, and differentiation of macrophages and monocytes. IL-34 functions in synergy with macrophage colony-stimulating factor (M-CSF or CSF1), which is another ligand for CSF1R, to regulate immune system homeostasis.

IL-34 is secreted by several cell types, including fibroblasts, keratinocytes, neuronal cells, and epithelial cells, and is expressed across different tissues, particularly in the spleen, brain, and kidneys. The broad tissue distribution of IL-34 underscores its involvement in immune modulation in diverse physiological contexts, including neuroinflammation, autoimmune diseases, and cancer. Its role is central to macrophage biology, impacting innate immune responses, tissue repair, and inflammatory processes.

Protein Structure

IL-34 is a glycoprotein with a predicted molecular weight of about 39 kDa, depending on the glycosylation pattern. The protein consists of 241 amino acids, and it shares minimal sequence homology with other interleukins or cytokines, which sets it apart as a unique member of the cytokine family.

Primary Structure:

• The IL34 gene is located on chromosome 16q22.1 in humans. It encodes a protein of 241 amino acids, with post-translational modifications contributing to its functional diversity.

Secondary and Tertiary Structure:

• The three-dimensional structure of IL-34 includes two long antiparallel β-sheets that form a β-sandwich fold. This structure is crucial for its interaction with CSF1R.
• IL-34 also undergoes N-linked glycosylation at several sites, which contributes to its stability and receptor-binding affinity. The glycosylation sites are primarily located in the N-terminal region, ensuring proper folding and secretion of the protein.

Quaternary Structure:

• IL-34 functions as a homodimer when binding to CSF1R. The homodimeric form is essential for effective signaling through the receptor, with each IL-34 monomer binding to a distinct site on CSF1R.

Interaction with CSF1R:

• IL-34 binds to CSF1R, a receptor tyrosine kinase, which triggers downstream signaling pathways important for macrophage and dendritic cell differentiation. IL-34 binds to the D2 and D3 domains of CSF1R, similar to M-CSF, but with slight differences in receptor affinity and signaling dynamics.

Classification and Subtypes

IL-34 is part of the cytokine family but is distinguished from traditional interleukins by its structural characteristics and binding properties. It is a ligand-specific cytokine for CSF1R, alongside M-CSF.

Subtypes:

IL-34 does not have different isoforms in the traditional sense. However, it shows functional diversity depending on its tissue expression, glycosylation patterns, and the cellular context in which it is expressed. Unlike some cytokines that have multiple receptor isoforms or splice variants, IL-34 acts specifically through CSF1R and exhibits no known receptor isoform preference.

Function and Biological Significance

IL-34 has several critical roles in immune homeostasis, particularly in regulating myeloid lineage cells such as macrophages, monocytes, and dendritic cells. The cytokine is involved in multiple biological processes:

Macrophage Differentiation and Survival:

• IL-34 promotes the differentiation, survival, and function of macrophages by binding to CSF1R. It stimulates macrophage proliferation and is essential for maintaining tissue-resident macrophages in organs such as the skin, brain, and kidney. IL-34 supports the expansion of macrophages in a manner similar to M-CSF, but with some tissue-specific differences.

Tissue-Specific Immune Functions:

• IL-34 is particularly important for maintaining microglia in the brain, contributing to neuroimmune regulation. Microglia are the resident macrophages of the brain, and IL-34 is critical for their proliferation and homeostasis in the central nervous system (CNS).
• In the skin, IL-34 is produced by keratinocytes and is involved in the local immune response, particularly in diseases like psoriasis where skin inflammation is prominent.

Modulation of Inflammatory Responses:

• IL-34 plays a role in inflammatory responses by regulating the secretion of pro-inflammatory cytokines and chemokines. Its activity enhances immune cell recruitment to sites of inflammation, particularly in the context of autoimmune diseases and chronic inflammation.

Neuroprotection:

• In the CNS, IL-34 is a crucial regulator of microglial function, influencing processes such as neuroinflammation, synaptic pruning, and neuroprotection. Dysregulation of IL-34 levels has been implicated in neurodegenerative diseases like Alzheimer’s disease.

Interaction with CSF1:

• IL-34 shares CSF1R as its receptor with M-CSF, but they display different tissue-specific expression and biological roles. For example, IL-34 is predominantly expressed in the brain and skin, while M-CSF is widely expressed in other tissues, highlighting non-redundant roles for these cytokines in immune regulation.

Clinical Issues

IL-34’s role in macrophage biology and immune regulation has linked it to various disease states, particularly in conditions involving chronic inflammation, autoimmune diseases, and neurodegenerative disorders.

Autoimmune Diseases:

• Elevated levels of IL-34 are associated with rheumatoid arthritis (RA), where it contributes to joint inflammation by promoting the survival of synovial macrophages and inducing TNF-α production. The high expression of IL-34 in synovial tissues correlates with disease severity, making it a potential biomarker and therapeutic target in RA.

Chronic Inflammatory Diseases:

• IL-34 is implicated in chronic inflammatory diseases such as psoriasis, where its expression in keratinocytes contributes to the recruitment of immune cells to the skin and the maintenance of inflammatory responses. Therapeutic strategies that target IL-34 signaling may help reduce the inflammatory burden in these conditions.

Neurodegenerative Disorders:

• Given its crucial role in microglial regulation, dysregulation of IL-34 has been linked to Alzheimer’s disease and other neurodegenerative disorders. Increased IL-34 expression has been observed in Alzheimer's patients, suggesting its involvement in disease progression by affecting microglial activity and neuroinflammation.

Cancer:

• IL-34 has been implicated in the tumor microenvironment, particularly in cancers such as pancreatic cancer, glioblastoma, and melanoma. It promotes the survival and proliferation of tumor-associated macrophages (TAMs), which support tumor growth and angiogenesis. Elevated IL-34 levels are associated with worse prognosis in several cancers due to its role in suppressing anti-tumor immunity.

Infectious Diseases:

• IL-34 has been implicated in chronic viral infections, including HIV and hepatitis B, where it contributes to immune cell activation and the persistence of inflammatory responses. Its role in regulating macrophages and dendritic cells during infection makes IL-34 a key player in pathogen control but also in the chronic immune activation seen in these infections.

Summary

IL-34 is a non-classical interleukin that plays a crucial role in regulating macrophage differentiation, immune responses, and inflammation by interacting with CSF1R. Structurally, IL-34 is a homodimeric glycoprotein that shares its receptor with M-CSF but exhibits tissue-specific expression and biological functions, particularly in the brain and skin. It is involved in various physiological and pathological processes, including immune homeostasis, chronic inflammatory diseases, neuroinflammation, and cancer.

Clinically, IL-34 has emerged as a potential biomarker and therapeutic target in diseases such as rheumatoid arthritis, psoriasis, Alzheimer’s disease, and cancer, where it regulates macrophage survival and inflammatory responses. Understanding its precise role in pathogen control, inflammatory signaling, and tissue-specific immune regulation continues to be an area of active research, with potential implications for immunotherapy and immune modulation strategies.