Biallelic CXCR2 loss-of-function mutations define a distinct congenital neutropenia entity

Abstract

Neutrophil homeostasis results from a balance between neutrophil production, release from the bone marrow and clearance from the circulation, where chemokines and their receptors play central roles. tudies on mice demonstrated that CXCR4 and CXCR2 receptors antagonistically regulate bone marrow neutrophil release. 2 While CXCR4 and its chemokine CXCL12, which is constitutively expressed in the bone marrow, provide key signals for neutrophil retention, CXCR2 activation by the CXCL8 subfamily of chemokines promotes their release from the bone marrow. Those events were shown in patients carrying heterozygous CXCR4 gain-of-function mutations causing the rare autosomal dominant WHIM syndrome, characterized by human papillomavirus-induced warts, hypogammaglobulinemia, recurrent bacterial infections and myelokathexis reflecting an accumulation of senescent neutrophils in the bone marrow. 3 Profound neutropenia associated with myelokathexis was previously reported in two siblings carrying a homozygous truncating CXCR2 loss-of-function mutation, supporting the importance of CXCR2 signaling in neutrophil mobilization. Myelokathexis and recurrent severe infections 5 in that single pedigree led to it being included in the large series of WHIM syndrome and WHIM syndrome-like cases, 6 and it remains the only published example of CXCR2 deficiency.