Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Mating System Homozygote x Homozygote         (Female x Male)   21-APR-09 Species laboratory mouse Generation N13+F2pN1F8 (25-JUN-09) Generation Definitions   Donating Investigator Craig Gerard,   Childrens' Hospital Boston, Harvard MS

Description
Mice homozygous for this CCR3 (chemokine (C-C motif) receptor 3) targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. No gene product (mRNA) is detected by RNA protection assay analysis of thymus, spleen and lung tissues. Mice homozygous for the mutation have impaired trafficking of eosinophils. A 7-fold decrease in the number of eosinophils in the small intestine and a 6-fold increase in the spleen is observed. Aerosol allergen challenge does not cause the expected infiltration of eosinophils to the lung tissue and airway lumens (50-70% reduction), although abundant eosinophils are found in the airway blood vessels. Concurrent increases in eosinophils in the spleen and intraepithelial mast cells in the spleen occur after allergen challenge. Homozygotes exhibit increased bronchoconstriction with allergen-induced airway hyperresponsiveness. There is no increase in eosinophils or eosinophil product major basic protein (MBP) in the skin after epicutaneous allergen treatment. Homozygous mice that have been epicutaneously sensitized do not develop increased airway responsiveness, or AHR, following inhalation challenge. These CCR3 mutant mice may be useful in studies of atopic dermatitis, allergic asthma, increased airway responsiveness/airway hyperresponsiveness (AHR).

Development
A targeting vector containing neomycin resistance and herpes simplex virus thymidine kinase genes driven by the phosphoglucokinase promoter was used to disrupt a 3kb region containing 39 bp of the region encoding the N-terminal, the start codon and a 5' untranslated region. The construct was electroporated into 129S4/SvJae derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into BALB/c blastocysts. The resulting chimeric animals were crossed to BALB/c mice, and then backcrossed to the same for 13 generations.

Control Information

	Control
	000651 BALB/cJ
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Ccr3^tm1Cge/Ccr3^tm1Cge

        involves: 129S4/SvJae * BALB/c

• immune system phenotype
• abnormal eosinophil cell number
  • homozygotes display a significant 7-fold decrease in the basal eosinophil content of the small intestine, along with a 6-fold increase in the spleen   (MGI Ref ID J:74509)
  • in contrast, the basal eosinophil content of lung tissue and thymus remains normal relative to wild-type mice   (MGI Ref ID J:74509)
• • decreased eosinophil cell number
    • homozygotes show a 7-fold reduction in the basal eosinophil content of the small intestine relative to wild-type mice   (MGI Ref ID J:74509)
    • in a model of allergic skin inflammation elicited by epicutaneous allergen application, eosinophils are virtually absent in the skin of homozygotes following epicutaneous OVA sensitization   (MGI Ref ID J:75347)
    • no eosinophil product MBP staining is detectable in either sham-sensitized or epicutaneously OVA-sensitized skin sites of homozygous mutant mice   (MGI Ref ID J:75347)
    • eosinophils are absent in bronchoalveolar lavage fluid after Aspergillus fumigatus exposure   (MGI Ref ID J:115273)
  • increased eosinophil cell number
    • naive homozygotes show a 6-fold increase in the basal eosinophil content of the spleen relative to naive wild-type mice, with eosinophils found in and around the red pulp areas, esp. under the capsule and out in the peripheral sinusoids of the spleen   (MGI Ref ID J:74509)
    • at 6 and 24 hrs after the last aerosolized ovalbumin (OA) challenge, homozygotes show an increase in splenic eosinophil numbers relative to wild-type mice, suggesting that eosinophils not recruited to sensitized and challenged lung home alternatively to the spleen   (MGI Ref ID J:74509)
• abnormal eosinophil physiology
  • homozygotes display impaired basal trafficking of eosinophils to the mucosal tissues of the gastrointestinal tract but not the lung   (MGI Ref ID J:74509)
  • in a model of allergic skin inflammation elicited by epicutaneous allergen application, homozygotes exhibit no increase in eosinophils or eosinophil product major basic protein (MBP) in the skin after epicutaneous sensitization with OVA   (MGI Ref ID J:75347)
  • homozygotes epicutaneously sensitized with OVA do not develop BAL or lung tissue eosinophilia following inhalation challenge with allergen   (MGI Ref ID J:75347)
• • impaired eosinophil chemotaxis
    • OA-challenged homozygotes display a selective reduction of eosinophil migration into the airways, with eosinophils abnormally trapped within the blood vessels and located under the endothelial cells instead of migrating out into the lung parenchyma   (MGI Ref ID J:74509)
  • impaired eosinophil recruitment
    • at 6 and 24 hrs after the last aerosolized OA challenge, sensitized challenged homozygotes show a 50%-70% decrease in eosinophil trafficking to both the airway lumen and lung tissue relative to wild-type mice   (MGI Ref ID J:74509)
    • homozygotes epicutaneously sensitized with OVA display impaired recruitment of eosinophils to the lung parenchyma and BAL fluid   (MGI Ref ID J:75347)
• abnormal mast cell physiology
  • OA-challenged homozygotes show a 4- to 12-fold increase in the number of mast cells found in the submucosal and epithelial layers of large bronchi relative to wild-type control mice, indicating increased mast cell trafficking within the airways after allergen challenge   (MGI Ref ID J:74509)
  • however, normal numbers of mast cells are found in the small intestine, skin, and spleen, indicating that this increase is specific to the airway   (MGI Ref ID J:74509)
• • increased mast cell degranulation
    • in some sections, intraepithelial mast cells found in OA-challenged homozygotes appear to be partially degranulated   (MGI Ref ID J:74509)
• decreased circulating interleukin-4 level
  • after Aspergillus fumigatus exposure   (MGI Ref ID J:115273)
• decreased monocyte cell number
  • reduced monocyte recruitment into bronchoalveolar lavage fluid after Aspergillus fumigatus exposure   (MGI Ref ID J:115273)
• respiratory system phenotype
• abnormal respiratory system physiology
  • reduced mucus production after Aspergillus fumigatus exposure   (MGI Ref ID J:115273)
• • abnormal airway responsiveness
    • homozygotes epicutaneously sensitized with OVA fail to develop increased airway responsiveness to methacholine following antigen inhalation   (MGI Ref ID J:75347)
  • • increased airway responsiveness
      • despite a marked reduction in eosinophil trafficking to the lung, OA-challenged homozygotes display a significantly greater airway hyperresponsiveness to inhaled methacholine relative to OA-challenged wild-type mice   (MGI Ref ID J:74509)
      • however, allergen challenge induces a normal Th2 response with respect to IL-4 and IL-13 levels, with no differences in serum levels of specific OA-IgE relative to wild-type mice   (MGI Ref ID J:74509)
• hematopoietic system phenotype
• *normal* hematopoietic system phenotype
  • homozygotes show normal T and B cell phenotypes and normal hematologic parameters, including leukocyte differential counts, platelets, and hematocrit   (MGI Ref ID J:75347)
• • abnormal eosinophil cell number
    • homozygotes display a significant 7-fold decrease in the basal eosinophil content of the small intestine, along with a 6-fold increase in the spleen   (MGI Ref ID J:74509)
    • in contrast, the basal eosinophil content of lung tissue and thymus remains normal relative to wild-type mice   (MGI Ref ID J:74509)
  • • decreased eosinophil cell number
      • homozygotes show a 7-fold reduction in the basal eosinophil content of the small intestine relative to wild-type mice   (MGI Ref ID J:74509)
      • in a model of allergic skin inflammation elicited by epicutaneous allergen application, eosinophils are virtually absent in the skin of homozygotes following epicutaneous OVA sensitization   (MGI Ref ID J:75347)
      • no eosinophil product MBP staining is detectable in either sham-sensitized or epicutaneously OVA-sensitized skin sites of homozygous mutant mice   (MGI Ref ID J:75347)
      • eosinophils are absent in bronchoalveolar lavage fluid after Aspergillus fumigatus exposure   (MGI Ref ID J:115273)
    • increased eosinophil cell number
      • naive homozygotes show a 6-fold increase in the basal eosinophil content of the spleen relative to naive wild-type mice, with eosinophils found in and around the red pulp areas, esp. under the capsule and out in the peripheral sinusoids of the spleen   (MGI Ref ID J:74509)
      • at 6 and 24 hrs after the last aerosolized ovalbumin (OA) challenge, homozygotes show an increase in splenic eosinophil numbers relative to wild-type mice, suggesting that eosinophils not recruited to sensitized and challenged lung home alternatively to the spleen   (MGI Ref ID J:74509)
  • decreased monocyte cell number
    • reduced monocyte recruitment into bronchoalveolar lavage fluid after Aspergillus fumigatus exposure   (MGI Ref ID J:115273)
• homeostasis/metabolism phenotype
• abnormal hemostasis
  • more modest increase in coagulation components after allergen stimulation than seen in controls   (MGI Ref ID J:115273)
• decreased circulating interleukin-4 level
  • after Aspergillus fumigatus exposure   (MGI Ref ID J:115273)
• cellular phenotype
• impaired eosinophil chemotaxis
  • OA-challenged homozygotes display a selective reduction of eosinophil migration into the airways, with eosinophils abnormally trapped within the blood vessels and located under the endothelial cells instead of migrating out into the lung parenchyma   (MGI Ref ID J:74509)

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Dermatology Research
Other

Hematological Research
Immunological Defects

Immunology, Inflammation and Autoimmunity Research
Autoimmunity
Immunodeficiency
      Asthma
      Inflammatory bowel disease
Inflammation
      Asthma
      Inflammatory bowel disease
Lymphoid Tissue Defects

Research Tools
Dermatology Research
Immunology and Inflammation Research

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Ccr3tm1Cge
Allele Name		targeted mutation 1, Craig Gerard
Allele Type		Targeted (knock-out)
Common Name(s)		CCR3 KO; CCR3-;
Mutation Made By		Craig Gerard,   Childrens' Hospital Boston, Harvard MS
Strain of Origin		129S4/SvJae
ES Cell Line Name		J1
ES Cell Line Strain		129S4/SvJae
Gene Symbol and Name		Ccr3, chemokine (C-C motif) receptor 3
Chromosome		9
Gene Common Name(s)		CC-CKR-3; CC-CKR3; CD193; CKR3; CMKBR3; Cmkbr3; MIP-1 alphaRL2;
Molecular Note		The gene was disrupted by replacement of a 3 kb region containing the start codon, 39 bp of the N-terminal coding region, and the 5' untranslated region with a PGK-neo cassette via homologous recombination. Absence of gene expression was confirmed by RT-PCR analysis of bone marrow mRNA from homozygous mutant animals. [MGI Ref ID J:74509]

Genotyping

Genotyping Information

Genotyping Protocols

Ccr3^tm1Cge, Melt Curve Analysis
Ccr3^tm1Cge, Standard PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Humbles AA; Lu B; Friend DS; Okinaga S; Lora J; Al-Garawi A; Martin TR; Gerard NP; Gerard C. 2002. The murine CCR3 receptor regulates both the role of eosinophils and mast cells in allergen-induced airway inflammation and hyperresponsiveness. Proc Natl Acad Sci U S A 99(3):1479-84. [PubMed: 11830666]  [MGI Ref ID J:74509]

Additional References

Ccr3^tm1Cge related

Abonia JP; Austen KF; Rollins BJ; Joshi SK; Flavell RA; Kuziel WA; Koni PA; Gurish MF. 2005. Constitutive homing of mast cell progenitors to the intestine depends on autologous expression of the chemokine receptor CXCR2. Blood 105(11):4308-13. [PubMed: 15705791]  [MGI Ref ID J:98967]

Chang LY; Lin YC; Kang CW; Hsu CY; Chu YY; Huang CT; Day YJ; Chen TC; Yeh CT; Lin CY. 2012. The indispensable role of CCR5 for in vivo suppressor function of tumor-derived CD103+ effector/memory regulatory T cells. J Immunol 189(2):567-74. [PubMed: 22664873]  [MGI Ref ID J:189562]

Chang LY; Lin YC; Mahalingam J; Huang CT; Chen TW; Kang CW; Peng HM; Chu YY; Chiang JM; Dutta A; Day YJ; Chen TC; Yeh CT; Lin CY. 2012. Tumor-Derived Chemokine CCL5 Enhances TGF-beta-Mediated Killing of CD8+ T Cells in Colon Cancer by T-Regulatory Cells. Cancer Res 72(5):1092-102. [PubMed: 22282655]  [MGI Ref ID J:181486]

Collington SJ; Westwick J; Williams TJ; Weller CL. 2010. The function of CCR3 on mouse bone marrow-derived mast cells in vitro. Immunology 129(1):115-24. [PubMed: 20050333]  [MGI Ref ID J:166196]

Fischer FR; Luo Y; Luo M; Santambrogio L; Dorf ME. 2001. RANTES-induced chemokine cascade in dendritic cells. J Immunol 167(3):1637-43. [PubMed: 11466387]  [MGI Ref ID J:120465]

Fulkerson PC; Fischetti CA; McBride ML; Hassman LM; Hogan SP; Rothenberg ME. 2006. A central regulatory role for eosinophils and the eotaxin/CCR3 axis in chronic experimental allergic airway inflammation. Proc Natl Acad Sci U S A 103(44):16418-23. [PubMed: 17060636]  [MGI Ref ID J:115273]

Fulkerson PC; Fischetti CA; Rothenberg ME. 2006. Eosinophils and CCR3 regulate interleukin-13 transgene-induced pulmonary remodeling. Am J Pathol 169(6):2117-26. [PubMed: 17148674]  [MGI Ref ID J:116219]

Fulkerson PC; Zhu H; Williams DA; Zimmermann N; Rothenberg ME. 2005. CXCL9 inhibits eosinophil responses by a CCR3- and Rac2-dependent mechanism. Blood 106(2):436-43. [PubMed: 15802529]  [MGI Ref ID J:107462]

Hallgren J; Jones TG; Abonia JP; Xing W; Humbles A; Austen KF; Gurish MF. 2007. Pulmonary CXCR2 regulates VCAM-1 and antigen-induced recruitment of mast cell progenitors. Proc Natl Acad Sci U S A 104(51):20478-83. [PubMed: 18077323]  [MGI Ref ID J:130586]

Ma W; Bryce PJ; Humbles AA; Laouini D; Yalcindag A; Alenius H; Friend DS; Oettgen HC; Gerard C; Geha RS. 2002. CCR3 is essential for skin eosinophilia and airway hyperresponsiveness in a murine model of allergic skin inflammation. J Clin Invest 109(5):621-8. [PubMed: 11877470]  [MGI Ref ID J:75347]

McKee AS; Munks MW; MacLeod MK; Fleenor CJ; Van Rooijen N; Kappler JW; Marrack P. 2009. Alum induces innate immune responses through macrophage and mast cell sensors, but these sensors are not required for alum to act as an adjuvant for specific immunity. J Immunol 183(7):4403-14. [PubMed: 19734227]  [MGI Ref ID J:152787]

Takeda A; Baffi JZ; Kleinman ME; Cho WG; Nozaki M; Yamada K; Kaneko H; Albuquerque RJ; Dridi S; Saito K; Raisler BJ; Budd SJ; Geisen P; Munitz A; Ambati BK; Green MG; Ishibashi T; Wright JD; Humbles AA; Gerard CJ; Ogura Y; Pan Y; Smith JR; Grisanti S; Hartnett ME; Rothenberg ME; Ambati J. 2009. CCR3 is a target for age-related macular degeneration diagnosis and therapy. Nature 460(7252):225-30. [PubMed: 19525930]  [MGI Ref ID J:150352]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice are bred as homozygotes.
Mating System	Homozygote x Homozygote         (Female x Male)   21-APR-09
Diet Information	LabDiet® 5K52/5K67

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls

Control Information

	Control
	000651 BALB/cJ
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

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The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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