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Coordinate regulation of neutrophil homeostasis by liver X receptors in mice
Cynthia Hong, … , Peter Tontonoz, Steven J. Bensinger
Cynthia Hong, … , Peter Tontonoz, Steven J. Bensinger
Published December 12, 2011
Citation Information: J Clin Invest. 2012;122(1):337-347. https://doi.org/10.1172/JCI58393.
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Research Article Immunology

Coordinate regulation of neutrophil homeostasis by liver X receptors in mice

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Abstract

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.

Authors

Cynthia Hong, Yoko Kidani, Noelia A-Gonzalez, Tram Phung, Ayaka Ito, Xin Rong, Katrin Ericson, Hanna Mikkola, Simon W. Beaven, Lloyd S. Miller, Wen-Hai Shao, Philip L. Cohen, Antonio Castrillo, Peter Tontonoz, Steven J. Bensinger

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Figure 1

LXR signaling regulates neutrophil homeostasis.

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LXR signaling regulates neutrophil homeostasis.
(A–C) Absolute neutrophi...
(A–C) Absolute neutrophil (A), leukocyte (B), and rbc (C) counts in peripheral blood of 6- to 8-week-old WT and LXRαβ–/– mice. Each point represents an individual mouse. P values are shown. (D) Representative FACS plots of Ly6GhiBrdU+ cells gated through CD11b+ in peripheral blood of 6- to 8-week-old WT and LXRαβ–/– mice on day 3 after BrdU injection (2 mg i.p.). Percent Ly6GhiBrdU+ cells is indicated within plots. (E) Frequency of Ly6Ghi BrdU+ cells gated through CD11b+ in peripheral blood of 6- to 8-week-old WT or LXRαβ–/– mice on the indicated days after BrdU pulse. n = 4 per group. (F) Absolute number of neutrophils in peripheral blood of 6- to 8-week-old WT mice fed chow compounded with 0.012% GW3965 or control chow for 3.5 days. n = 3 per group. Data are representative of 2 experiments. **P < 0.01.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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