title: Coordinate regulation of neutrophil homeostasis by liver X receptors in mice.
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.affiliation: Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hong
authors.forename: Yoko
authors.initials: Y
authors.lastname: Kidani
authors.forename: Noelia
authors.initials: N
authors.lastname: A-Gonzalez
authors.forename: Tram
authors.initials: T
authors.lastname: Phung
authors.forename: Ayaka
authors.initials: A
authors.lastname: Ito
authors.forename: Xin
authors.initials: X
authors.lastname: Rong
authors.forename: Katrin
authors.initials: K
authors.lastname: Ericson
authors.forename: Hanna
authors.initials: H
authors.lastname: Mikkola
authors.forename: Simon W
authors.initials: SW
authors.lastname: Beaven
authors.forename: Lloyd S
authors.initials: LS
authors.lastname: Miller
authors.forename: Wen-Hai
authors.initials: WH
authors.lastname: Shao
authors.forename: Philip L
authors.initials: PL
authors.lastname: Cohen
authors.forename: Antonio
authors.initials: A
authors.lastname: Castrillo
authors.forename: Peter
authors.initials: P
authors.lastname: Tontonoz
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Bensinger
mesh_terms: D000818:Animals; D017209:Apoptosis; D016922:Cellular Senescence; D016207:Cytokines / Q000235:genetics; D025461:Feedback, Physiological; D015870:Gene Expression; D006706:Homeostasis; D020381:Interleukin-17 / Q000235:genetics / Q000378:metabolism; D053760:Interleukin-23 Subunit p19 / Q000235:genetics / Q000378:metabolism; D050356:Lipid Metabolism; D008099:Liver / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism*; D057093:Orphan Nuclear Receptors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D010587:Phagocytosis; D015398:Signal Transduction; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D016207:Cytokines; C098680:Il17a protein, mouse; C508841:Il23a protein, mouse; D020381:Interleukin-17; D053760:Interleukin-23 Subunit p19; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors