Coordinate regulation of neutrophil homeostasis by liver X receptors in mice

The most abundant immune cell type is the neutrophil, a key first responder after pathogen invasion. Neutrophil numbers in the periphery are tightly regulated to prevent opportunistic infections and aberrant inflammation. In healthy individuals, more than 1 × 10⁹ neutrophils per kilogram body weight...

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Bibliographic Details
Published in:The Journal of clinical investigation 2012-01, Vol.122 (1), p.337-347
Main Authors: Hong, Cynthia, Kidani, Yoko, A-Gonzalez, Noelia, Phung, Tram, Ito, Ayaka, Rong, Xin, Ericson, Katrin, Mikkola, Hanna, Beaven, Simon W, Miller, Lloyd S, Shao, Wen-Hai, Cohen, Philip L, Castrillo, Antonio, Tontonoz, Peter, Bensinger, Steven J
Format: Article
Language:English
Subjects:
Animals
Apoptosis
Biomedical research
Bone marrow
Care and treatment
Cellular Senescence
Cytokines
Cytokines - genetics
Diagnosis
Feedback, Physiological
Gene Expression
Homeostasis
Inflammation
Interleukin-17 - genetics
Interleukin-17 - metabolism
Interleukin-23 Subunit p19 - genetics
Interleukin-23 Subunit p19 - metabolism
Leukocytes
Lipid Metabolism
Lipids
Liver
Liver - cytology
Liver - immunology
Liver - metabolism
Liver X Receptors
Metabolism
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Neutrophils
Neutrophils - immunology
Neutrophils - metabolism
Orphan Nuclear Receptors - deficiency
Orphan Nuclear Receptors - genetics
Orphan Nuclear Receptors - metabolism
Phagocytosis
Physiological aspects
Risk factors
Signal Transduction
Spleen - cytology
Spleen - immunology
Spleen - metabolism
Systemic lupus erythematosus
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Summary:The most abundant immune cell type is the neutrophil, a key first responder after pathogen invasion. Neutrophil numbers in the periphery are tightly regulated to prevent opportunistic infections and aberrant inflammation. In healthy individuals, more than 1 × 10⁹ neutrophils per kilogram body weight are released from the bone marrow every 24 hours. To maintain homeostatic levels, an equivalent number of senescent cells must be cleared from circulation. Recent studies indicate that clearance of senescent neutrophils by resident tissue macrophages and DCs helps to set homeostatic levels of neutrophils via effects on the IL-23/IL-17/G-CSF cytokine axis, which stimulates neutrophil production in the bone marrow. However, the molecular events in phagocytes underlying this feedback loop have remained indeterminate. Liver X receptors (LXRs) are members of the nuclear receptor superfamily that regulate both lipid metabolic and inflammatory gene expression. Here, we demonstrate that LXRs contribute to the control of neutrophil homeostasis. Using gain- and loss-of-function models, we found that LXR signaling regulated the efficient clearance of senescent neutrophils by peripheral tissue APCs in a Mer-dependent manner. Furthermore, activation of LXR by engulfed neutrophils directly repressed the IL-23/IL-17/G-CSF granulopoietic cytokine cascade. These results provide mechanistic insight into the molecular events orchestrating neutrophil homeostasis and advance our understanding of LXRs as integrators of phagocyte function, lipid metabolism, and cytokine gene expression.
ISSN:0021-9738
1558-8238
DOI:10.1172/jci58393