Abstract
Expression levels of CX3CR1 (C-X3-C motif chemokine receptor 1) on immune cells have significant importance in maintaining tissue homeostasis under physiological and pathological conditions. The factors implicated in the regulation of CX3CR1 and its specific ligand CX3CL1 (fractalkine) expression remain largely unknown. Recent studies provide evidence that host's misfolded proteins occurring in the forms of polymers or amyloid fibrils can regulate CX3CR1 expression. Herein, a novel example demonstrates that polymers of human ZZ alpha-1 antitrypsin (Z-AAT) protein, resulting from its conformational misfolding due to the Z (Glu342Lys) mutation in SERPINA1 gene, strongly lower CX3CR1 mRNA expression in human peripheral blood mononuclear cells (PBMCs). This parallels with increase of intracellular levels of CX3CR1 and Z-AAT proteins. Presented data indicate the involvement of the CX3CR1 pathway in the Z-AAT-related disorders and further support the role of misfolded proteins in CX3CR1 regulation.
Highlights
Interactions between the chemokine receptors and chemokines, and other proteins, peptides, lipids, and microbial products, play a critical role in the recruitment of inflammatory cells into injured/diseased tissues[1]
Since CX3CR1/CX3CL1 axis is involved in the synthesis of anti-inflammatory cytokines and has a significant role in cytoskeletal rearrangement, migration, apoptosis and proliferation, its dysregulation is associated with the development of cardiovascular diseases, kidney ischemia–reperfusion injury, cancer, chronic obstructive pulmonary disease (COPD), neurodegenerative disorders and others[5,6,7]
Homozygous Z alpha-1 antitrypsin deficiency (AATD) mutation is the most clinically relevant among Caucasians that is characterized by low plasma levels of AAT protein (10-15% compared to the wild type, MM AAT, 1.3-2 g/L) and the presence of intracellular and circulating ZZ alpha-1 antitrypsin (Z-AAT) polymers[13]
Summary
Interactions between the chemokine receptors and chemokines, and other proteins, peptides, lipids, and microbial products, play a critical role in the recruitment of inflammatory cells into injured/diseased tissues[1]. Many human diseases involve altered surface expression of chemokine receptors, which can lead to a defective cell migration and inappropriate immune response. In the central nervous system, CX3CR1 is largely expressed by microglial cells (brain macrophages)[3], which are involved in neurodegenerative diseases like. Alzheimers peptide, Aβ, interacts with CX3CR1 and significantly reduces its expression in cultured microglial cells and in Alzheimers brain[11]. Highly aggregated extracellular Tau protein binds to CX3CR1, promotes its internalization and reduces expression in microglial cells[12]. Polymers of human Z alpha-1 antitrypsin (Z-AAT), resulting from protein misfolding due to the Z (Glu342Lys) mutation in SERPINA1 gene, lower CX3CR1 mRNA in human PBMCs, which parallels with increased intracellular CX3CR1 and Z-AAT protein levels
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