Osteocytes regulate neutrophil development through IL-19: a potent cytokine for neutropenia treatment

Abstract

Osteocytes are the most abundant (90-95%) cells in bone and have emerged as an important regulator of hematopoiesis, but their role in neutrophil development and the underlying mechanisms remain unclear. Interleukin (IL)-19 produced predominantly by osteocytes stimulated granulopoiesis and neutrophil formation, which stimulated IL-19 receptor (IL-20Rb)/Stat3 signaling in neutrophil progenitors to promote their expansion and neutrophil formation. Mice with constitutive activation of the mechanistic target of rapamycin complex (mTORC1) signaling in osteocytes (Dmp1-Cre) exhibited a dramatic increase in IL-19 production and promyelocytes/myelocytic expansion, while mTORC1 inactivation in osteocytes reduced IL-19 production and neutrophil number in mice. We showed that IL-19 administration stimulated neutrophil development, while neutralizing endogenous IL-19 or depletion of its receptor inhibited the process. Importantly, low dose IL-19 reversed chemotherapy, irradiation, or chloramphenicol-induced neutropenia in mice more efficiently than G-CSF. These evidence indicated that IL-19 was an essential regulator of neutrophil development and a potent cytokine for neutropenia treatment.

The Protective Effects of Osteocyte‐Derived Extracellular Vesicles Against Alzheimer's Disease Diminished with Aging

“…To further confirm these results, Dmp1 Cre mice expressing Cre recombinase under the control of the murine Dmp1 promoter were used as an alternative tool to generate osteocyte specific targeted mutants. [ 21 ] The obtained Dmp1 Cre ;Cd63 fl/+ mice (genotyping identified in Figure S2 B,D, Supporting Information) showed similar eGFP and mCherry expression in the cortex area of brain sections (Figure S3 A,B, Supporting Information). Although Dmp1 Cre mice were widely used in osteocyte‐specific targeting, previous evidence had revealed that it also targeted cells in the mouse cerebellum and hindbrain.…”

Osteocytes regulate organismal senescence of bone and bone marrow

“…Previous studies have reported that osteocyte regulates myelopoiesis via Gs α -dependent and -independent signaling(Fulzele, et al 2013; Azab, et al 2020). Recent study also reported that osteocyte mTORC1 signaling regulates granulopoiesis via secreted IL-19(Xiao, et al 2021). Meanwhile, sclerostin secreted by osteocyte adversely affects B cell survival(Horowitz and Fretz 2012).…”

“…Osteocytes, as the long living terminally differentiated cells and the most abundant cells within the bone matrix(Tresguerres et al 2020), play vital roles in maintaining the skeletal homeostasis. Apart from mechanical transduction(Long 2011; Sato et al 2020), osteocytes have been shown to regulate bone formation, bone resorption, bone marrow hematopoiesis(Asada et al 2013; Azab et al 2020; Fulzele et al 2013; Xiao et al 2021) and generate endocrine signals to mediate function of other organs(Razzaque 2009; Fulzele et al 2017; Cain et al 2012). Here we hypothesize that osteocytes, may exert another important role in regulation of lineage cell fate specifications, and harmonization of bone and bone marrow through mediation of organismal senescence.…”

Elevated IL-19 Serum Levels in Patients With Pernicious Anemia and Autoimmune Gastritis

“…It still remains unknown whether IL-19 has additional effects on other organs or tissues but its potential application in neutropenic state is undoubted, being more efficient than granulocyte colony-stimulating factor (G-CSF). Cancer patients who underwent chemotherapy and had reduced activity to promote bone marrow neutrophil formation, had striking downregulation of serum IL-19 ( 24 ).…”