12/15-Lipoxygenase Regulates the Inflammatory Response to Bacterial Products In Vivo

• Published in: The Journal of immunology (1950) Vol. 181; no. 9; pp. 6514 - 6524
• Main Authors: Dioszeghy, Vincent, Rosas, Marcela, Maskrey, Benjamin H, Colmont, Chantal, Topley, Nicholas, Chaitidis, Pavlos, Kuhn, Hartmut, Jones, Simon A, Taylor, Philip R, O'Donnell, Valerie B
• Format: Journal Article
• Language: English
• Published: United States Am Assoc Immnol 01.11.2008
• Subjects: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid - biosynthesis; 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid - physiology; Acute Disease; Animals; Arachidonate 12-Lipoxygenase - biosynthesis; Arachidonate 12-Lipoxygenase - deficiency; Arachidonate 12-Lipoxygenase - physiology; Arachidonate 15-Lipoxygenase - biosynthesis; Arachidonate 15-Lipoxygenase - deficiency; Arachidonate 15-Lipoxygenase - physiology; Cells, Cultured; Cytokines - biosynthesis; Cytokines - metabolism; Cytokines - physiology; Hydroxyeicosatetraenoic Acids - biosynthesis; Hydroxyeicosatetraenoic Acids - physiology; Immunophenotyping; Inflammation Mediators - metabolism; Inflammation Mediators - physiology; Macrophages, Peritoneal - enzymology; Macrophages, Peritoneal - microbiology; Macrophages, Peritoneal - pathology; Mice; Mice, Inbred C57BL; Mice, Knockout; Peritonitis - enzymology; Peritonitis - immunology; Peritonitis - microbiology; Staphylococcal Infections - enzymology; Staphylococcal Infections - immunology; Staphylococcal Infections - pathology; Staphylococcus epidermidis - immunology; Staphylococcus epidermidis - metabolism
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.181.9.6514

The peritoneal macrophage (Mphi) is the site of greatest 12/15-lipoxygenase (12/15-LOX) expression in the mouse; however, its immunoregulatory role in this tissue has not been explored. Herein, we show that 12/15-LOX is expressed by 95% of resident peritoneal CD11b(high) cells, with the remaining 5% being 12/15-LOX(-). 12/15-LOX(+) cells are phenotypically defined by high F4/80, SR-A, and Siglec1 expression, and enhanced IL-10 and G-CSF generation. In contrast, 12/15-LOX(-) cells are a dendritic cell population. Resident peritoneal Mphi numbers were significantly increased in 12/15-LOX(-/-) mice, suggesting alterations in migratory trafficking or cell differentiation in vivo. In vitro, Mphi from 12/15-LOX(-/-) mice exhibit multiple abnormalities in the regulation of cytokine/growth factor production both basally and after stimulation with Staphylococcus epidermidis cell-free supernatant. Resident adherent cells from 12/15-LOX(-/-) mice generate more IL-1, IL-3, GM-CSF, and IL-17, but less CCL5/RANTES than do cells from wild-type mice, while Staphylococcus epidermidis cell-free supernatant-elicited 12/15-LOX(-/-) adherent cells release less IL-12p40, IL-12p70, and RANTES, but more GM-CSF. This indicates a selective effect of 12/15-LOX on peritoneal cell cytokine production. In acute sterile peritonitis, 12/15-LOX(+) cells and LOX products were cleared, then reappeared during the resolution phase. The peritoneal lavage of 12/15-LOX(-/-) mice showed elevated TGF-beta1, along with increased immigration of monocytes/Mphi, but decreases in several cytokines including RANTES/CCL5, MCP-1/CCL2, G-CSF, IL-12-p40, IL-17, and TNF-alpha. No changes in neutrophil or lymphocyte numbers were seen. In summary, endogenous 12/15-LOX defines the resident MPhi population and regulates both the recruitment of monocytes/Mphi and cytokine response to bacterial products in vivo.