Mice Lacking Both Granulocyte Colony-Stimulating Factor (CSF) and Granulocyte-Macrophage CSF Have Impaired Reproductive Capacity, Perturbed Neonatal Granulopoiesis, Lung Disease, Amyloidosis, and Reduced Long-Term Survival

Abstract

Mice lacking granulocyte colony-stimulating factor (G-CSF) are neutropenic with reduced hematopoietic progenitors in the bone marrow and spleen, whereas those lacking granulocyte-macrophage colony-stimulating factor (GM-CSF) have impaired pulmonary homeostasis and increased splenic hematopoietic progenitors, but unimpaired steady-state hematopoiesis. These contrasting phenotypes establish unique roles for these factors in vivo, but do not exclude the existence of additional redundant functions. To investigate this issue, we generated animals lacking both G-CSF and GM-CSF. In the process of characterizing the phenotype of these animals, we further analyzed G-CSF– and GM-CSF–deficient mice, expanding the recognized spectrum of defects in both. G-CSF–deficient animals have a marked predisposition to spontaneous infections, a reduced long-term survival, and a high incidence of reactive type AA amyloidosis. GM-CSF–deficient mice have a modest impairment of reproductive capacity, a propensity to develop lung and soft-tissue infections, and a similarly reduced survival as in G-CSF–deficient animals. The phenotype of mice lacking both G-CSF and GM-CSF was additive to the features of the constituent genotypes, with three novel additional features: a greater degree of neutropenia among newborn mice than in those lacking G-CSF alone, an increased neonatal mortality rate, and a dominant influence of the lack of G-CSF on splenic hematopoiesis resulting in significantly reduced numbers of splenic progenitors. In contrast to newborn animals, adult mice lacking both G-CSF and GM-CSF exhibited similar neutrophil levels as G-CSF–deficient animals. These findings demonstrate that the additional lack of GM-CSF in G-CSF–deficient animals further impairs steady-state granulopoiesis in vivo selectively during the early postnatal period, expand the recognized roles of both G-CSF and GM-CSF in vivo, and emphasize the utility of studying multiply deficient mouse strains in the investigation of functional redundancy.

Piglets produced from cloned blastocysts cultured in vitro with GM‐CSF

“…The importance of GM-CSF on pregnancy is well demonstrated (Seymour et al, 1997;Robertson et al, 1999), although specific mechanisms of GM-CSF on embryos are still under investigation. It is thought that one of the mechanisms by which GM-CSF improves development is that it can protect embryos against apoptosis.…”

Expression of serum- and glucocorticoid-regulated kinase (sgk) mRNA is up-regulated by GM-CSF and other proinflammatory mediators in human granulocytes

“…It is generally believed that GM-CSF, released by host cells at the site of inflammation, enhances the ability of infiltrating neutrophils to fight infection. In support of this hypothesis, GM-CSF knockout mice show no gross abnormalities of hematopoiesis, but do have an increased propensity to develop both lung and soft-tissue infections [25,26].…”

Complement 3 deficiency impairs early pregnancy in mice

“…Oviduct produces GM-CSF as an embryotrophic molecule. Although GM-CSF-deficient mice are fertile (Stanley et al, 1994), the sizes of their offsprings are smaller at birth (Seymour et al, 1997). Compared with the wild-type animals, GM-CSF knockout mice also have smaller litter size, higher rate of resorption and malformed fetuses ß 2009 WILEY-LISS, INC.…”