Effect of C-C chemokine receptor 2 (CCR2) knockout on type-2 (schistosomal antigen-elicited) pulmonary granuloma formation: analysis of cellular recruitment and cytokine responses.
Monocyte chemotactic protein (MCP)-1 is postulated to play a role in cellular recruitment during inflammatory reactions. C-C chemokine receptor 2 (CCR2) is considered the major G-protein coupled receptor for MCP-1/JE. We reported that mice with knockout of the CCR2 gene display partially impaired type-1 granuloma formation. The present study similarly examined the effect of CCR2 deficiency on synchronously developing type-2 (Th2) cytokine-mediated lung granulomas elicited by embolization of beads coated with Ags of Schistosoma mansoni eggs. Systemically, blood monocytes were reduced by about half throughout the 8-day study period. At the local level, granuloma size and macrophage content were impaired during the early growth phase (days 1 to 2). By day 4, granuloma sizes were similar to controls. In granulomatous lungs, CCR2 knockout increased mRNA for CCR2 agonists, MCP-1, MCP-3, and MCP-5, but reduced IL-4 and IFNgamma mRNA. The latter was possibly related to decreased CD4+ T cell recruitment. Regionally, draining lymph nodes showed panlymphoid hyperplasia with impaired production of IFNgamma, IL-2, and IL-4, but not IL-5, IL-10, or IL-13. Analysis of procollagen gene expression indicated transient impairment of procollagen III transcripts on day 4 of granuloma formation. These findings indicate that agonists of CCR2 contribute to multiple facets of type-2 hypersensitivity granulomatous inflammation.
D000818:Animals; D000947:Antigens, Helminth / Q000276:immunology*; D002478:Cells, Cultured; D018925:Chemokines / Q000235:genetics; D002633:Chemotaxis / Q000502:physiology; D003094:Collagen / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis*; D015870:Gene Expression; D006099:Granuloma / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008171:Lung Diseases / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000096:biosynthesis; D054390:Receptors, CCR2; D019707:Receptors, Chemokine / Q000235:genetics*; D012550:Schistosoma mansoni / Q000276:immunology*