A chemotaxis model to explain WHIM neutrophil accumulation in the bone marrow of WHIM mouse model.

ABSTRACT

Neutrophils are essential immune cells that defend the host against pathogenic microbial agents. Neutrophils are produced in the bone marrow and are retained there through CXCR4-CXCL12 signaling. However, patients with the Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome are prone to infections due to increased accumulation of neutrophils in the bone marrow leading to low numbers of circulating neutrophils. How neutrophils accumulate in the bone marrow in this condition is poorly understood. To better understand factors involved in neutrophil accumulation in the bone marrow, neutrophils from wildtype and WHIM mouse models were characterized in their response to CXCL12 stimulation. WHIM neutrophils were found to exert stronger traction forces, formed significantly more lamellipodia-type protrusions and migrated with increased speed and displacement upon CXCL12 stimulation as compared to wildtype cells. Migration speed of WHIM neutrophils showed a larger initial increase upon CXCL12 stimulation, which decayed over a longer time period as compared to wildtype cells. We proposed a computational model based on the chemotactic behavior of neutrophils that indicated increased CXCL12 sensitivity and prolonged CXCR4 internalization adaptation time in WHIM neutrophils as being responsible for increased accumulation in the bone marrow. These findings provide a mechanistic understanding of bone marrow neutrophil accumulation in WHIM condition and novel insights into restoring neutrophil regulation in WHIM patients.