Functional defect of peripheral neutrophils in mice with induced deletion of CXCR2

Abstract

Type 2 CXC chemokine receptor CXCR2 plays roles in development, tumorigenesis and inflammation. CXCR2 also promotes demyelination and decreases remyelination by actions toward hematopoietic cells and non-hematopoietic cells. Germline CXCR2 deficient (Cxcr2−/−) mice reported in 1994 revealed the complexity of CXCR2 function and its differential expression in varied cell-types. Here, we describe Cxcr2fl/fl mice for which the targeting construct was generated by recombineering based on homologous recombination in E. coli. Without recombination Cxcr2fl/fl mice have CXCR2 expression on neutrophils in peripheral blood, bone marrow and spleen. Cxcr2fl/fl mice were crossed to Mx-Cre mice in which Cre recombinase is induced by type I interferons, elicited by injection with polyinosinic-polycytidylic acid (poly(I:C)). CXCR2-deficient neutrophils were observed in poly(I:C) treated Cxcr2fl/fl::Mx-Cre+ (Cxcr2-CKO) mice, but not in poly(I:C) treated Cxcr2f//+::Mx-Cre+ mice. CXCR2 deletion was mainly observed peripherally but not in the CNS. Cxcr2-CKO mice showed impaired neutrophil migration in sterile peritonitis. Cxcr2-CKO mice reported here will provide a genetic reagent to dissect roles of CXCR2 in the neutrophil granulocyte lineage. Furthermore Cxcr2fl/fl mice will provide useful genetic models to evaluate CXCR2 function in varied cell populations.

Chronic systemic IL-1β exacerbates central neuroinflammation independently of the blood–brain barrier integrity

“…On the other hand, central TNF has been associated with demyelination and oligodendrocyte cytotoxicity (Hiremath et al, 2008;Probert et al, 1995;Selmaj and Raine, 1988). CXCR2 is also a molecule strongly associated with the recruitment of neutrophils (Charo and Ransohoff, 2006;Liu et al, 2013;Veenstra and Ransohoff, 2012). We found an up-regulation of CXCR2 in the exacerbated lesion, which is concomitant with the influx of neutrophils after the peripheral stimulation.…”

Danirixin: A Reversible and Selective Antagonist of the CXC Chemokine Receptor 2

“…As neutrophils age, CXCR4 levels increase and CXCR2 levels decrease, leading to either a return to the bone marrow or a decrease in migration to CXCR2 ligands (Rankin, 2010). Mice engineered to have a deletion in CXCR2 showed impaired neutrophil migration (Liu et al, 2013), and hyperfunctional CXCR4 in severe combined immunodeficiency mice have accumulation of neutrophils in the bone marrow (Rankin, 2010). In the CXCR2-deficient mice, CXCL1 was not efficiently scavenged in mice with greater than 90% deletion, but in mice with a less pronounced deletion, there was no defect in scavenging (Liu et al, 2013).…”

An interferon-β-resistant and NLRP3 inflammasome–independent subtype of EAE with neuronal damage

“…The Asc −/− and Nlrp3 −/− mice were gifts from Genentech under material transfer agreement (MTA), and were rederived in our facility. Cxcr2 fl/fl mice were a gift from Dr. Richard M. Ransohoff (Cleveland Clinic) 47 . C57BL/6 and Lck-Cre transgenic mice were purchased from Jackson Laboratories.…”