Table 2.

Characteristics of genetic models of inducible and constitutive neutropenia.

	Mice	Neutrophil numbers	Advantages	Potential limitations	References
Inducible	PMNDTR (hMRP8-Cre iDTRfl)	▪ Marked reduction (>90%) in blood, spleen, bone marrow and lung neutrophils upon DT injection	▪ Normal number of neutrophils until injection of DT ▪ Neutrophil population can be restored in DT-treated PMNDTR mice upon adoptive transfer of DTR− neutrophils	▪ DT injection reduces levels of blood and spleen monocytes ▪ Depletion is transient and needs repetitive injections for long-term experiments ▪ Possible off-target or other side effects of repeated treatment with DT	(6)
Constitutive	CXCR2−/−	▪ Reduction of 60% of blood neutrophils ▪ No reduction of spleen neutrophils and higher counts of bone marrow mature neutrophils	▪ Neutrophil population can be restored upon adoptive transfer of WT neutrophils ▪ Depletion effective from birth and does not require any treatment	▪ High numbers of residual neutrophils ▪ Also expressed by other cell populations (such as monocytes/macrophages, mast cells, endothelial and epithelial cells) ▪ Side effects caused by CXCR2 deficiency such as neutrophil-independent exaggeration of inflammatory reactions	(113)
	G-CSFR−/−	▪ Reduction of 80 and 50% of blood and bone marrow neutrophils	▪ Neutrophil population can be restored upon adoptive transfer of WT neutrophils ▪ Depletion effective from birth and does not require any treatment	▪ High numbers of residual neutrophils ▪ Side effects caused by G-CSFR deficiency ▪ Potential appearance of compensatory mechanisms due to constitutive neutrophil deficiency	(104)
	Gfi-1−/−	▪ Quasi absence of mature neutrophil numbers in the blood, spleen and bone marrow	▪ Neutrophil population can be restored upon adoptive transfer of WT neutrophils ▪ Depletion effective from birth and does not require any treatment	▪ Emergence of an abnormal myeloid cell population that can induce inflammation reactions ▪ Thymus aplasia ▪ Abnormal differentiation of immune cell populations (such as dendritic cells, iNKT cells and T-cells) ▪ Potential appearance of compensatory mechanisms due to constitutive neutrophil deficiency ▪ Aberrant production of cytokines ▪ Manifestation of eye inflammation and abscesses ▪ Behavior abnormalities (ataxia, no response to noise and head tilt) ▪ Delayed growth and high mortality	(124, 130)
	Ella-Cre Gfi-1fl/fl	▪ NA	▪ Neutrophil population can be restored upon adoptive transfer of WT neutrophils ▪ Depletion effective from birth and does not require any treatment ▪ Gfi-1fl/fl mice could be used to restrict the mutation to neutrophils	▪ Emergence of an abnormal myeloid cell population that can induce inflammation reactions ▪ Delayed growth and high mortality of Ella-Cre+; Gfi-1fl/fl mice ▪ 10–20% of Gfi-1fl/fl mice exhibited features of Gfi-1−/− mice, such as reduced body size, even with no Cre expression ▪ Thymus aplasia ▪ Potential appearance of compensatory mechanisms due to constitutive neutrophil deficiency	(131, 133)
	Gfi-1GFP/GFP	▪ Quasi absence of mature neutrophil numbers in the blood and bone marrow	▪ Neutrophil population can be restored upon adoptive transfer of WT neutrophils ▪ Depletion effective from birth and does not require any treatment ▪ Gfi-1 expressing cells are GFP+ and allow the study of Gfi-1 expressing cells	▪ Emergence of an abnormal myeloid cell population that is capable of inducing inflammation reactions ▪ Thymus aplasia ▪ Abnormal differentiation of immune cell populations (such as T-cells) ▪ Potential appearance of compensatory mechanisms due to constitutive neutrophil deficiency ▪ Delayed growth and high mortality	(134, 135)
	Genista (Gfi-1C318Y)	▪ Marked reduction (around 90%) in blood neutrophils	▪ Normal growth and mortality, even in conventional non-SPF conditions ▪ Normal T and B cell differentiation and function ▪ Neutrophil population can be restored upon adoptive transfer of WT neutrophils ▪ Depletion effective from birth and does not require any treatment	▪ Impaired responsiveness of NK cells ▪ Emergence of abnormal CD11b+/Ly-6Gint myeloid cells capable of sustaining inflammatory processes ▪ Thymus aplasia ▪ Potential appearance of compensatory mechanisms due to constitutive neutrophil deficiency	(142, 143)
	LysM-Cre Mcl-1fl/fl	▪ 3-fold decrease in circulating neutrophils ▪ High percentage of apoptotic neutrophils	▪ Neutrophil population can be restored upon adoptive transfer of WT neutrophils ▪ Depletion effective from birth and does not require any treatment	▪ High numbers of residual neutrophils escaping deletion ▪ Knock-out of Lysozyme M ▪ Appearance of compensatory mechanisms due to constitutive neutrophil deficiency	(153)
	LysMCre/Cre- Mcl-1fl/fl	▪ Marked reduction of neutrophil counts in the blood (98%), spleen and bone marrow (>93%).	▪ Most of the other immune cell populations seem unaffected by the mutation ▪ Neutrophil population can be restored upon adoptive transfer of WT neutrophils ▪ Depletion effective from birth and does not require any treatment	▪ Decrease in bone marrow B cells and increase in splenic macrophages ▪ Higher mortality rate and reduced offspring numbers in SPF and non-SPF conditions ▪ Knock-out of Lysozyme M ▪ Potential appearance of compensatory mechanisms due to constitutive neutrophil deficiency	(7)
	hMRP8-Cre Mcl-1fl/fl	▪ Marked reduction (>99%) in blood neutrophil counts	▪ Other immune cell populations seem unaffected by the mutation ▪ Neutrophil population can be restored upon adoptive transfer of WT neutrophils ▪ Depletion effective from birth and does not require any treatment	▪ High mortality (only 30% survival at 1 year of age) ▪ Low breeding productivity ▪ Appearance of compensatory mechanisms due to constitutive neutrophil deficiency	(7)
	Foxo3a −/−	▪ 50% reduction of circulating neutrophils	▪ Neutrophil population can be restored upon adoptive transfer of WT neutrophils ▪ Depletion effective from birth and does not require any treatment	▪ High numbers of apoptotic neutrophils ▪ Exaggerated lymphoproliferation and more prone to inflammation reactions ▪ Overactivated T-helper cells	(157)