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Impaired host defense, hematopoiesis, granulomatous inflammation and type 1-type 2 cytokine balance in mice lacking CC chemokine receptor 1.

Gao JL, Wynn TA, Chang Y, Lee EJ, Broxmeyer HE, Cooper S, Tiffany HL, Westphal H, Kwon-Chung J, Murphy PM - J. Exp. Med. (1997)

Bottom Line: To test the role of CCR1 in granuloma formation, we injected Schistosoma mansoni eggs intravenously, and observed a 40% reduction in the size of lung granulomas in -/- mice compared to +/+ littermates.This was associated with increased interferon-gamma and decreased interleukin-4 production in -/- versus +/+ lung lymph node cells stimulated with egg-specific antigen, suggesting that CCR1 influences the inflammatory response not only through direct effects on leukocyte chemotaxis, but also through effects on the type 1-type 2 cytokine balance.Thus CCR1 has nonredundant functions in hematopoiesis, host defense, and inflammation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Host Defenses,National Institute of Allergy and Infectio us Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT
CC chemokine receptor 1 (CCR1) is expressed in neutrophils, monocytes, lymphocytes, and eosinophils, and binds the leukocyte chemoattractant and hematopoiesis regulator macrophage inflammatory protein (MIP)-1alpha, as well as several related CC chemokines. Four other CCR subtypes are known; their leukocyte and chemokine specificities overlap with, but are not identical to, CCR1, suggesting that CCR1 has both redundant and specific biologic roles. To test this, we have developed CCR1-deficient mice (-/-) by targeted gene disruption. Although the distribution of mature leukocytes was normal, steady state and induced trafficking and proliferation of myeloid progenitor cells were disordered in -/- mice. Moreover, mature neutrophils from -/- mice failed to chemotax in vitro and failed to mobilize into peripheral blood in vivo in response to MIP-1alpha. Consistent with this, -/- mice had accelerated mortality when challenged with Aspergillus fumigatus, a fungus controlled principally by neutrophils. To test the role of CCR1 in granuloma formation, we injected Schistosoma mansoni eggs intravenously, and observed a 40% reduction in the size of lung granulomas in -/- mice compared to +/+ littermates. This was associated with increased interferon-gamma and decreased interleukin-4 production in -/- versus +/+ lung lymph node cells stimulated with egg-specific antigen, suggesting that CCR1 influences the inflammatory response not only through direct effects on leukocyte chemotaxis, but also through effects on the type 1-type 2 cytokine balance. Thus CCR1 has nonredundant functions in hematopoiesis, host defense, and inflammation.

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Disordered myeloid progenitor cell proliferation in CCR1  −/− mice. The protocol used and mice evaluated were the same as for  Table 2. Significance for −/− compared to +/+ mice given control diluent: a, P <0.05; b, P <0.005; c, P <0.001. Significance for −/− mice  given lps compared to +/+ mice given lps: d, P <0.001.
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Figure 2: Disordered myeloid progenitor cell proliferation in CCR1 −/− mice. The protocol used and mice evaluated were the same as for Table 2. Significance for −/− compared to +/+ mice given control diluent: a, P <0.05; b, P <0.005; c, P <0.001. Significance for −/− mice given lps compared to +/+ mice given lps: d, P <0.001.

Mentions: We also assessed the proliferative status of myeloid progenitors in the marrow and spleen of CCR1 −/− and +/+ mice under steady-state and lps-perturbed conditions. Under steady-state conditions (mice given control diluent), progenitors were proliferating in the marrow as determined by the percentage in S phase, whereas progenitors in the spleen were in a slow or noncycling state (compare especially CFU-GM and CFU-GEMM). In CCR1 +/+ and −/− mice not given lps, no significant differences in cycling rates were observed for any progenitor subtype in either marrow or spleen (Fig. 2). However, significant differences were found in progenitor cell proliferation after lps administration to the mice. This was evident in the spleen, but not marrow, where lps induced a rapid proliferation of progenitors in CCR1 +/+, but not in CCR1 −/− mice. Thus, CCR1 may regulate both steady-state and induced movement during adult life of myeloid progenitor cells from marrow to spleen and blood, as well as the resultant proliferative status of these stimulated cells.


Impaired host defense, hematopoiesis, granulomatous inflammation and type 1-type 2 cytokine balance in mice lacking CC chemokine receptor 1.

Gao JL, Wynn TA, Chang Y, Lee EJ, Broxmeyer HE, Cooper S, Tiffany HL, Westphal H, Kwon-Chung J, Murphy PM - J. Exp. Med. (1997)

Disordered myeloid progenitor cell proliferation in CCR1  −/− mice. The protocol used and mice evaluated were the same as for  Table 2. Significance for −/− compared to +/+ mice given control diluent: a, P <0.05; b, P <0.005; c, P <0.001. Significance for −/− mice  given lps compared to +/+ mice given lps: d, P <0.001.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2196337&req=5

Figure 2: Disordered myeloid progenitor cell proliferation in CCR1 −/− mice. The protocol used and mice evaluated were the same as for Table 2. Significance for −/− compared to +/+ mice given control diluent: a, P <0.05; b, P <0.005; c, P <0.001. Significance for −/− mice given lps compared to +/+ mice given lps: d, P <0.001.
Mentions: We also assessed the proliferative status of myeloid progenitors in the marrow and spleen of CCR1 −/− and +/+ mice under steady-state and lps-perturbed conditions. Under steady-state conditions (mice given control diluent), progenitors were proliferating in the marrow as determined by the percentage in S phase, whereas progenitors in the spleen were in a slow or noncycling state (compare especially CFU-GM and CFU-GEMM). In CCR1 +/+ and −/− mice not given lps, no significant differences in cycling rates were observed for any progenitor subtype in either marrow or spleen (Fig. 2). However, significant differences were found in progenitor cell proliferation after lps administration to the mice. This was evident in the spleen, but not marrow, where lps induced a rapid proliferation of progenitors in CCR1 +/+, but not in CCR1 −/− mice. Thus, CCR1 may regulate both steady-state and induced movement during adult life of myeloid progenitor cells from marrow to spleen and blood, as well as the resultant proliferative status of these stimulated cells.

Bottom Line: To test the role of CCR1 in granuloma formation, we injected Schistosoma mansoni eggs intravenously, and observed a 40% reduction in the size of lung granulomas in -/- mice compared to +/+ littermates.This was associated with increased interferon-gamma and decreased interleukin-4 production in -/- versus +/+ lung lymph node cells stimulated with egg-specific antigen, suggesting that CCR1 influences the inflammatory response not only through direct effects on leukocyte chemotaxis, but also through effects on the type 1-type 2 cytokine balance.Thus CCR1 has nonredundant functions in hematopoiesis, host defense, and inflammation.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Host Defenses,National Institute of Allergy and Infectio us Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT
CC chemokine receptor 1 (CCR1) is expressed in neutrophils, monocytes, lymphocytes, and eosinophils, and binds the leukocyte chemoattractant and hematopoiesis regulator macrophage inflammatory protein (MIP)-1alpha, as well as several related CC chemokines. Four other CCR subtypes are known; their leukocyte and chemokine specificities overlap with, but are not identical to, CCR1, suggesting that CCR1 has both redundant and specific biologic roles. To test this, we have developed CCR1-deficient mice (-/-) by targeted gene disruption. Although the distribution of mature leukocytes was normal, steady state and induced trafficking and proliferation of myeloid progenitor cells were disordered in -/- mice. Moreover, mature neutrophils from -/- mice failed to chemotax in vitro and failed to mobilize into peripheral blood in vivo in response to MIP-1alpha. Consistent with this, -/- mice had accelerated mortality when challenged with Aspergillus fumigatus, a fungus controlled principally by neutrophils. To test the role of CCR1 in granuloma formation, we injected Schistosoma mansoni eggs intravenously, and observed a 40% reduction in the size of lung granulomas in -/- mice compared to +/+ littermates. This was associated with increased interferon-gamma and decreased interleukin-4 production in -/- versus +/+ lung lymph node cells stimulated with egg-specific antigen, suggesting that CCR1 influences the inflammatory response not only through direct effects on leukocyte chemotaxis, but also through effects on the type 1-type 2 cytokine balance. Thus CCR1 has nonredundant functions in hematopoiesis, host defense, and inflammation.

Show MeSH
Related in: MedlinePlus