Interleukin-34, a comprehensive review

IL-34 is a novel cytokine that was identified in 2008 in a comprehensive proteomic analysis as a tissue-specific ligand of CSF-1 receptor (CSF-1R). IL-34 exists in all vertebrates including fish, amphibians, birds, and mammals, showing high conservation among species. Structurally, IL-34 belongs to the short-chain helical hematopoietic cytokine family but shows no apparent consensus structural domains, motifs, or sequence homology with other cytokines. IL-34 is synthesized as a secreted homodimeric glycoprotein that binds to the extracellular domains of CSF-1R and receptor-type protein-tyrosine phosphatase-zeta (PTP-ζ) in addition to the chondroitin sulfate chains of syndecan-1. These interactions result in activating several signaling pathways that regulate major cellular functions, including proliferation, differentiation, survival, metabolism, and cytokine/chemokine expression in addition to cellular adhesion and migration. In the steady state, IL-34 contributes to the development and maintenance of specific myeloid cell subsets in a tissue-specific manner: Langerhans cells in the skin and microglia in the brain. In pathological conditions, changes in IL-34 expression-increased or decreased-are involved in disease pathogenesis and correlate with progression, severity, and chronicity. One decade after its discovery, IL-34 has been introduced as a newcomer to the big family of interleukins with specific physiological functions, critical pathological roles, and promising clinical applications in disease diagnosis and treatment. In this review, we celebrate the 10th anniversary of IL-34 discovery, introducing its biological characteristics, and discussing the importance of IL-34 signaling network in health and disease.