Proper desensitization of CXCR4 is required for lymphocyte development and peripheral compartmentalization in mice

Abstract

Desensitization controls G protein-dependent signaling of chemokine receptors. We investigate the physiologic implication of this process for CXCR4 in a mouse model harboring a heterozygous mutation of the Cxcr4 gene, which engenders a desensitization-resistant receptor. Such anomaly is linked to the warts, hypogammaglobulinemia, infections, myelokathexis (WHIM) syndrome, a human rare combined immunodeficiency. Cxcr4(+/mutant(1013)) mice display leukocytes with enhanced responses to Cxcl12 and exhibit leukopenia as reported in patients. Treatment with CXCL12/CXCR4 antagonists transiently reverses blood anomalies, further demonstrating the causal role of the mutant receptor in the leukopenia. Strikingly, neutropenia occurs in a context of normal bone marrow architecture and granulocyte lineage maturation, indicating a minor role for Cxcr4-dependent signaling in those processes. In contrast, Cxcr4(+/1013) mice show defective thymopoiesis and B-cell development, accounting for circulating lymphopenia. Concomitantly, mature T and B cells are abnormally compartmentalized in the periphery, with a reduction of primary follicles in the spleen and their absence in lymph nodes mirrored by an unfurling of the T-cell zone. These mice provide a model to decipher the role of CXCR4 desensitization in the homeostasis of B and T cells and to investigate which manifestations of patients with WHIM syndrome may be overcome by dampening the gain of CXCR4 function.

Targeting CXCR4-dependent immunosuppressive Ly6C low monocytes improves antiangiogenic therapy in colorectal cancer

“…axis in regulation of immune cells has been investigated, including a subset of monocytes (i.e., Ly6C high monocytes) (12)(13)(14)(15)(16)(17), whether CXCR4 is involved in regulation of another subset of monocytes (i.e., Ly6C low monocytes) is not known.…”

CCR1 Inhibition Ameliorates the Progression of Lupus Nephritis in NZB/W Mice

“…After incubation with the 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) substrate (Sigma-Aldrich), the reaction was stopped by adding 0.05 M citric acid and 0.01% sodium azide, and the plates were read at OD 405 nm . Total levels of IgG, IgM, and IgA were determined as described previously (32). Serum concentrations of TNF-a, IL-1b, IL-6, and IL-10 were assessed using a standardized ELISA (Quantikine R&D Systems, Rochester, MN).…”

“…After standardized mechanical dissociation with a gentleMACS Dissociator (Miltenyi Biotec, Bergisch Gladbach, Germany), cells were filtered through a 70-mm-pore nylon mesh (BD Biosciences, San Jose, CA), and erythrocytes were lysed with an ammonium-chloridepotassium buffer. Cells were harvested from mouse spleens as described (32) …”

A phase 1 clinical trial of long-term, low-dose treatment of WHIM syndrome with the CXCR4 antagonist plerixafor

“…5,6 The mechanism appears to involve loss of negative regulatory elements, 7,8 which is thought to increase CXCR4 signaling and the normal adhesion-promoting function of CXCR4 for neutrophils in bone marrow, among other effects. [9][10][11] Granulocyte colony-stimulating factor (G-CSF) and intravenous immunoglobulin (IVIg) have been documented to prevent infections in patients with severe congenital neutropenia and hypogammaglobulinemia, respectively. 12,13 Both treatments have been used in WHIM patients; however, no studies have documented clinical efficacy, and they are nonspecific, expensive, difficult to administer, and of questionable efficacy in controlling infections and warts.…”