Neutrophils protect the host by migrating from the blood to the tissues to engulf, destroy and clear microbial pathogens. Sufficient numbers of neutrophils are required for host defense, but excessive neutrophil accumulation and activation can cause tissue injury. Hence, circulating neutrophil counts and neutrophil production in the bone marrow are tightly controlled. Understanding the mechanisms that regulate neutrophil production and release could yield novel ways to treat disease. Mice deficient in the adhesion molecule CD18 or the small GTPase Rac2 have elevated numbers of neutrophils in the bone marrow and circulation, and their neutrophils exhibit multiple defects in migration and activation. Therefore, the neutrophilia observed in CD18-/- and Rac2-/- mice may be due to host defense defects that stimulate granulopoiesis in the bone marrow and a cell-intrinsic requirement for CD18 or Rac2 in regulating neutrophil production and release. Our studies tested the hypothesis that CD18 and Rac2 regulate neutrophil production. Our studies examined the direct role of CD18 and Rac2 in regulating neutrophil production, and the contribution of extrinsic factors to neutrophilia in CD18 or Rac2 deficiency.
Neutrophilia in CD18 or Rac2 deficiency is largely suppressed in the presence of wild type (WT) leukocytes that can protect the host against pathogens, indicating that defects in host defense contribute to the neutrophilia observed in CD18 or Rac2 deficiency. However, the proportion of CD18-/- or Rac2-/- leukocytes that are neutrophils is increased despite the presence of normal leukocytes within the same host, indicating that CD18 and Rac2 may regulate leukocyte production directly. CD18 limits the survival of neutrophils and/or their precursors in the bone marrow, which may contribute to the increased number of neutrophils in CD18 deficiency. Rac2 in hematopoietic cells regulates neutrophil production in two ways: indirectly through its role in mediating neutrophil recruitment and activation for host defense, and directly through mechanisms that regulate the lineage distribution of leukocytes. Rac2 expressed in non-hematopoietic cells may participate in modulating circulating neutrophil counts. Thus, both CD18 and Rac2 have unexpected roles in regulating neutrophil production and release that are distinct from their roles in mediating neutrophil recruitment and activation for host defense.