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(American Journal of Pathology. 2000;157:2055-2063.)
© 2000 American Society for Investigative Pathology

Regular Articles

Chemokine Receptor 1 Knockout Abrogates Natural Killer Cell Recruitment and Impairs Type-1 Cytokines in Lymphoid Tissue during Pulmonary Granuloma Formation

Xiaozhou Shang^*, Boqin Qiu^*, Kirsten A. Frait, Jerry S. Hu^*, Joanne Sonstein, Jeffrey L. Curtis, Bao Lu^§, Craig Gerard^§ and Stephen W. Chensue^*

From the Department of Pathology,^*
University of Michigan Hospitals, Ann Arbor, Michigan; the Departments of Pathology and Laboratory Medicine
and Pulmonary Medicine,
Veterans Affairs Medical Center, Ann Arbor, Michigan; and the Childrens Hospital,^§
Harvard Medical School, Boston, Massachusetts

Mice with targeted mutation of chemokine receptor 1 (CCR1) were used to assess the contribution of CCR1 agonists to local, regional, and systemic inflammatory-related events during experimental pulmonary granuloma formation. Models of Th1 (type-1) and Th2 (type-2) cell-mediated lung granulomas were induced in wild-type (CCR+/+) and knockout (CCR1-/-) mice by embolizing Sepharose beads coupled to the purified protein derivative of Mycobacterium bovis or soluble antigens derived from Schistosoma mansoni eggs. Morphometric analysis indicated that granuloma sizes were unchanged in CCR1-/- mice, but flow cytometric analyses of dispersed granulomas revealed that natural killer cell recruitment to type-1 lesions was abrogated by 60%. Analysis of cytokine production by draining lymph node cultures showed altered expression in CCR1-/- mice characterized by reduced interleukin-2 and interferon- in the type-1 response, and enhanced interleukin-5 and interleukin-13 in the type-2 response. Peripheral blood leukocytosis was also enhanced in the type-1 but not the type-2 response. These findings suggest that CCR1 agonists contribute to multiple immunoinflammatory events in the type-1 granulomatous response with natural killer cell accumulation being particularly sensitive to CCR1 disruption. Although functional efficacy of granulomas may be altered, chemokine redundancy and cytokine reserve seem to make the bulk of the exudative response resistant to CCR1 disruption.

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