Improved Antibacterial Host Defense and Altered Peripheral Granulocyte Homeostasis in Mice Lacking the Adhesion Class G Protein Receptor CD97

Abstract

CD97 is a member of the adhesion family of G protein-coupled receptors. Alternatively spliced forms of CD97 bind integrins ␣5␤1 and ␣v␤3, decay accelerating factor, or dermatan sulfate. CD97 is expressed on myeloid cells at high levels and a variety of other cell types at lower levels. Little is known about the physiological function of CD97. To begin dissecting the function of CD97, we evaluated the immune response of CD97 null mice to systemic infection by Listeria monocytogenes. CD97 null mice were significantly more resistant to listeriosis than matched wild-type mice. A major determinant of the difference in survival appeared to be the comparatively more robust accumulation of granulocytes in the blood and in infected livers of CD97 null mice within 18 h of inoculation, correlating with a decrease in the number of bacteria. CD97 null mice also displayed a mild granulocytosis in the nonchallenged state. Because there is a strong suggestion that CD97 functions in an adhesive capacity, we examined the migratory properties of granulocytes in CD97 null mice. In chimeric animals, CD97 null and wild-type granulocytes migrated similarly, as determined by inflammationinduced emigration from the bone marrow and accumulation in the peritoneum. Granulocyte development in the bone marrow of CD97 null mice was comparable to that of wild-type mice, and CD97 deficiency did not appear to stimulate granulocytosis secondary to peripheral inflammation and resultant granulocyte colonystimulating factor induction, unlike various other models of adhesion deficiencies. Our results suggest that CD97 plays a role in peripheral granulocyte homeostasis.

Analysis of CD97 Expression and Manipulation: Antibody Treatment but Not Gene Targeting Curtails Granulocyte Migration

“…Next to basic parameters like weight and size, breeding, and life span, our analyses included a thorough anatomical survey of the architecture of essentially all organs as well as a detailed investigation of the hematopoietic compartment. Our findings confirm and extend results recently obtained by Kelly and coworkers from an independently generated Cd97 Ϫ/Ϫ mouse (27). Reportedly, this mouse was better protected against an acute infection with L. monocytogenes.…”

“…Although this slight elevation of granulocyte numbers in blood was also observed in our Cd97 Ϫ/Ϫ mouse, we could not find any evidence of improved antibacterial host defense in pneumococcal pneumonia. Furthermore, Kelly and coworkers showed that in mixed bone marrow chimeric animals, CD97-deficient and wild-type granulocytes accumulated similarly in blood and peritoneum in response to inflammatory stimuli (27). Also, our Cd97 Ϫ/Ϫ mouse showed no altered migration of granulocytes into the peritoneal cavity following application of thioglycollate.…”

“…Genetic models for CD97 became available only recently. A CD97-deficient mouse developed by Kelly and coworkers displayed an increased resistance to systemic infection by Listeria monocytogenes, possibly caused by a mild granulocytosis (27). Unexpectedly, however, granulocyte recruitment to the peritoneum in response to inflammatory stimuli was normal in this mouse.…”

Thy-1 (CD90) Is an Interacting Partner for CD97 on Activated Endothelial Cells

“…Targeting mouse CD97 by mAb inhibited the accumulation of neutrophils at sites of inflammation, thereby affecting antibacterial host defense (36) and inflammatory disorders (37). Otherwise, accumulation of PMNC at sites of inflammation was not affected in CD97-deficient mice (20,38) that display no overt phenotype at steady-state, except for a mild granulocytosis, which increases under inflammatory conditions. Interestingly, application of CD97 mAb blocked neutrophil trafficking after thioglycollate-induced peritonitis in wild-type, but not in CD97 knockout, mice (20).…”

GPS autoproteolysis is required for CD97 to up-regulate the expression of N-cadherin that promotes homotypic cell-cell aggregation

“…Thus, CD55 binds strongly to CD97(125) but weakly to CD97(1235) and CD97 (1)(2)(3)(4)(5) [23]; chondroitin sulfate binds only to CD97 (1)(2)(3)(4)(5) [24]; a5b1 and avb3 integrins bind to all CD97 isoforms via a RGD motif in the stalk region [25]. Abbreviations: 7TM, seven-transmembrane; ECD, ectodomain; EDTA, 2,2 0 ,2 00 ,2 000 -(ethane-1,2-diyldinitrilo)tetraacetic acid; EGF-TM7, epidermal growth factor module-containing seven-transmembrane receptor; EGTA, glycol-bis(2-aminoethylether)-N,N,N 0 ,N 0 -tetraacetic acid; Fc, fragment crystallisable; GPCR, G proteincoupled receptor; GPS, GPCR proteolysis site; WT, wild-type Functional studies using specific Abs, recombinant CD97 proteins, and knock-out animals have revealed a role for CD97 in leukocyte migration, recruitment and activation [26][27][28][29]. In addition, CD97 is known to be involved in angiogenesis and the migration and invasion of tumor cells [20,25,30].…”