Increased granulopoiesis through interleukin-17 and granulocyte colony-stimulating factor in leukocyte adhesion molecule–deficient mice

Abstract

Many mutant mice deficient in leukocyte adhesion molecules display altered hematopoiesis and neutrophilia. This study investigated whether peripheral blood neutrophil concentrations in these mice are elevated as a result of accumulation of neutrophils in the circulation or altered hematopoiesis mediated by a disrupted regulatory feedback loop. Chimeric mice were generated by transplanting various ratios of CD18 ؉/؉ and CD18 ؊/؊ unfractionated bone marrow cells into lethally irradiated wild-type mice, resulting in approximately 0%, 10%, 50%, 90%, or 100% CD18 null neutrophils in the blood. The presence of only 10% CD18 ؉/؉ neutrophils was sufficient to prevent the severe neutrophilia seen in mice reconstituted with CD18 ؊/؊ bone marrow cells. These data show that the neutrophilia in CD18 ؊/؊ mice is not caused by enhanced neutrophil survival or the inability of neutrophils to leave the vascular compartment. In CD18 ؊/؊ , CD18 ؊/؊ E ؊/؊ , CD18 ؊/؊ P ؊/؊ , EP ؊/؊ , and EPI ؊/؊ mice, levels of granulocyte colony-stimulating factor (G-CSF) and interleukin-17 (IL-17) were elevated in proportion to the neutrophilia seen in these mice, regardless of the underlying mutation. Antibiotic treatment or the propensity to develop skin lesions did not correlate with neutrophil counts. Blocking IL-17 or G-CSF function in vivo significantly reduced neutrophil counts in severely neutrophilic mice by approximately 50% (P < .05) or 70% (P < .01), respectively. These data show that peripheral blood neutrophil numbers are regulated by a feedback loop involving G-CSF and IL-17 and that this feedback loop is disrupted when neutrophils cannot migrate into peripheral tissues. IntroductionAdhesion molecule-deficient mice have provided valuable information in elucidating leukocyte recruitment mechanisms. Many of the mice deficient in leukocyte adhesion molecules display secondary phenotypes, including altered hematopoiesis and neutrophilia, which have not been fully investigated. Mice lacking P-selectin, leukocyte function-associated antigen-1, intercellular adhesion molecule-1 (ICAM-1), core-2 glucosaminyltransferase, P-and L-selectin, P-selectin and ICAM-1, or L-selectin and ICAM-1 are mildly neutrophilic. [1][2][3][4][5][6][7] Mice deficient in multiple leukocyte adhesion molecules, including CD18 integrins; E-and P-selectin; Eand P-selectin and ICAM-1; E-, P-, and L-selectin; E-, P-, and L-selectin and ICAM-1; CD18 and E-selectin; and CD18 and P-selectin show more severe neutrophilia. 3,[8][9][10][11][12][13][14] A few adhesion molecule-deficient mice, including mice lacking Mac-1, Eselectin, or both E-and L-selectin, have normal circulating neutrophil concentrations. 2,3,15 Although the existence of physiologic mechanisms controlling peripheral neutrophil counts has been proposed as early as 1991, 16 the reason for elevated neutrophil counts in adhesion molecule knockout mice is not known. One candidate mechanism for neutrophilia is passive accumulation of circulating neutrophils because of altered neutrophil survival. Although mice l...

Retracted: α‐GalCer ameliorates listeriosis by accelerating infiltration of Gr‐1+ cells into the liver

“…Numerous cytokines such as GM-CSF, IL-3, IL-6, IL-11, and SCF promote granulopoiesis by themselves and/or in concert with G-CSF [9,10]. G-CSF is indispensable for both steady-state and emergency granulopoiesis [11][12][13][14], and IL-17 regulates G-CSF secretion [9,10,[15][16][17][18]. In addition to Gr-1 1 cells, g/d T cells also participate in early protection against L. monocytogenes infection [19][20][21][22].…”

“…Yet, a recent study using transcriptome analysis revealed that mRNA expression of GM-CSF and IL-17, but not IL-3, IL-6, IL-11, G-CSF and SCF, is up-regulated by iNKT cells immediately (1 h) after a-GalCer treatment [72], and IL-17 has recently been shown to be secreted by iNKT cells lacking NK1.1 surface expression [73]. Since (i) GM-CSF and IL-17 play a crucial role in granulopoiesis [9,10,[15][16][17][18] and (ii) numbers of Gr-1 1 cells were numerically increased after a-GalCer treatment, we wondered whether increase in liver Gr-1 1 cells following a-GalCer treatment was due to accelerated granulopoiesis. To address this issue, we first examined secretion of GM-CSF and IL-17 after a-GalCer treatment by intracellular cytokine staining.…”

Neutrophils in cancer: neutral no more

“…In this feedback mechanism, macrophages and dendritic cells phagocytose apoptotic neutrophils [47][48][49] , curbing the secretion of IL-23 46 -a cytokine that controls IL-17 expression by αβ T cells, γδ T cells, innate lymphoid cells and other lymphocytes 50,51 . Because IL-17 is upstream of G-CSF 52,53 , lower levels of IL-17 equate to reduced expression of G-CSF and steady-state release of neutrophils from the bone marrow 46 . Commensal bacteria and enterocyte-derived CXCL5 in the gut also play a role in neutrophil homeostasis by increasing or inhibiting IL-17 production, respectively 54,55 .…”

Epidermal phospholipase Cδ1 regulates granulocyte counts and systemic interleukin-17 levels in mice

“…We therefore speculated that granulocytosis in PLCδ1 − / − mice was induced by humoural factors secreted from peripheral tissues. IL-17 is a critical cytokine for granulopoiesis [13][14][15] , and we, therefore, assessed serum IL-17 concentrations. IL-17 levels in the serum of control mice were below the detection limit, but those in PLCδ1 − / − mice were detectable (Fig.…”

“…Interleukin (IL)-17, also called IL-17A, is a pleiotropic cytokine that has emerged as a central player in the mammalian immune system, with important roles in the pathology of many disease processes, including allergic responses 4 and autoimmune diseases [5][6][7][8][9][10] . IL-17 is mainly produced by T lymphocytes under the regulation of IL-23 (refs 11,12), and in turn, regulates granulopoiesis through induction of granulocyte colony-stimulating factor (G-CSF) [13][14][15] . Granulocytes are key players in the pathogenesis of several inflammatory diseases.…”