Chelation of Free Zn2+ Impairs Chemotaxis, Phagocytosis, Oxidative Burst, Degranulation, and Cytokine Production by Neutrophil Granulocytes

• Published in: Biological trace element research Vol. 171; no. 1; pp. 79 - 88
• Main Authors: Hasan, Rafah, Lothar Rink, Hajo Haase
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.05.2016
• Subjects: Biochemistry; Biomedical and Life Sciences; Biotechnology; Cell Degranulation; chelating agents; Chelating Agents - chemistry; Chelating Agents - metabolism; chelation; chemoattractants; Chemotaxis; Cytokines - biosynthesis; Humans; in vivo studies; inflammation; interleukin-8; laboratory animals; Life Sciences; microorganisms; neutrophils; Neutrophils - cytology; Neutrophils - metabolism; Nutrition; Oncology; Phagocytosis; Respiratory Burst; secretion; zinc; Zinc - chemistry; Zinc - metabolism; TPEN; Neutrophil granulocytes; Chemotaxis; Zinc; Phagocytosis; Oxidative burst
• ISSN: 0163-4984; 1559-0720
• DOI: 10.1007/s12011-015-0515-0

Neutrophil granulocytes are the largest leukocyte population in the blood and major players in the innate immune response. Impaired neutrophil function has been reported in in vivo studies with zinc-deficient human subjects and experimental animals. Moreover, in vitro formation of neutrophil extracellular traps has been shown to depend on free intracellular Zn²⁺. This study investigates the requirement of Zn²⁺ for several other essential neutrophil functions, such as chemotaxis, phagocytosis, cytokine production, and degranulation. To exclude artifacts resulting from indirect effects of zinc deprivation, such as impaired hematopoietic development and influences of other immune cells, direct effects of zinc deprivation were tested in vitro using cells isolated from healthy human donors. Chelation of Zn²⁺ by the membrane permeable chelator N,N,N′,N′-tetrakis-(2-pyridylmethyl)-ethylenediamine (TPEN) reduced granulocyte migration toward N-formyl-L-methionyl-L-leucyl-L-phenylalanine (fMLF) and IL-8, indicating a role of free intracellular Zn²⁺ in chemotaxis. However, a direct action of Zn²⁺ as a chemoattractant, as previously reported by others, was not observed. Similar to chemotaxis, phagocytosis, oxidative burst, and granule release were also impaired in TPEN-treated granulocytes. Moreover, Zn²⁺ contributes to the regulatory role of neutrophil granulocytes in the inflammatory response by affecting the cytokine production by these cells. TPEN inhibited the lipopolysaccharide-induced secretion of chemotactic IL-8 and also anti-inflammatory IL-1ra. In conclusion, free intracellular Zn²⁺ plays essential roles in multiple neutrophil functions, affecting extravasation to the site of the infection, uptake and killing of microorganisms, and inflammation.