New models for analyzing mast cell functions in vivo

Trends in Immunology

Volumn 33, Issue 12, 2012, Pages 613-625

  Reber, Laurent L ^a   Marichal, Thomas ^a   Galli, Stephen J ^a  

^a STANFORD UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

Basophils; C kit; Cre recombinase; Mouse model

Indexed keywords

CHYMASE; CRE RECOMBINASE; DIPHTHERIA TOXIN; HELODERMIN; IMMUNOGLOBULIN E; INTERLEUKIN 10; INTERLEUKIN 4; MAST CELL ASSOCIATED PROTEASE CARBOXYPEPTIDASE A3; MAST CELL PROTEASE 4; MAST CELL PROTEASE 5; MAST CELL PROTEASE 6; MAST CELL PROTEASE 7; PROTEIN MCL 1; PROTEIN TYROSINE PHOSPHATASE SHP 2; SERINE PROTEINASE; STEM CELL FACTOR; UNCLASSIFIED DRUG;

ADAPTIVE IMMUNITY; ALLERGIC ENCEPHALITIS; ARTHRITIS; ASTHMA; C57BL 6 MOUSE; CELL FUNCTION; CONGESTIVE HEART FAILURE; DENDRITIC CELL; DISEASE EXACERBATION; ENGRAFTMENT; GENE; GENE DELETION; GENE EXPRESSION; GENE INACTIVATION; GENE MUTATION; GENE TARGETING; HEMATOPOIETIC STEM CELL; HOST RESISTANCE; IN VITRO STUDY; IN VIVO STUDY; MAST CELL; MELANOCYTE; NONHUMAN; ONCOGENE C KIT; PASSIVE SKIN ANAPHYLAXIS; PHOSPHATASE AND TENSIN HOMOLOG GENE; PROMOTER REGION; REVIEW; SURVIVAL FACTOR; TRANSGENIC MOUSE; WILD TYPE;

ANIMALS; GENE DELETION; HUMANS; MAST CELLS; MODELS, IMMUNOLOGICAL; MUTATION; PROTO-ONCOGENE PROTEINS C-KIT;

EID: 84869877668     PISSN: 14714906     EISSN: 14714981     Source Type: Journal    
DOI: 10.1016/j.it.2012.09.008     Document Type: Review

References (140)

1. Oka T., et al. Evidence questioning cromolyn's effectiveness and selectivity as a 'mast cell stabilizer' in mice. Lab. Invest. 2012, 92:1472-1482.
2. Oliveira S.H., Lukacs N.W. Stem cell factor: a hemopoietic cytokine with important targets in asthma. Curr. Drug Targets Inflamm. Allergy 2003, 2:313-318.
3. Reber L., et al. Stem cell factor and its receptor c-Kit as targets for inflammatory diseases. Eur. J. Pharmacol. 2006, 533:327-340.
4. Kitamura Y. Heterogeneity of mast cells and phenotypic change between subpopulations. Annu. Rev. Immunol. 1989, 7:59-76.
5. Galli S.J., et al. Mast cells as "tunable" effector and immunoregulatory cells: recent advances. Annu. Rev. Immunol. 2005, 23:749-786.
6. W-sh/W-sh mice as a model for investigating mast cell biology in vivo. Am. J. Pathol. 2005, 167:835-848.
7. Dawicki W., Marshall J.S. New and emerging roles for mast cells in host defence. Curr. Opin. Immunol. 2007, 19:31-38.
8. W-sh/W-sh mice. Am. J. Pathol. 2010, 176:926-938.
9. Galli S.J., et al. Mast cells in the development of adaptive immune responses. Nat. Immunol. 2005, 6:135-142.
10. Grimbaldeston M.A., et al. Effector and potential immunoregulatory roles of mast cells in IgE-associated acquired immune responses. Curr. Opin. Immunol. 2006, 18:751-760.
11. Grimbaldeston M.A., et al. Mast cell-derived interleukin 10 limits skin pathology in contact dermatitis and chronic irradiation with ultraviolet B. Nat. Immunol. 2007, 8:1095-1104.
12. W-sh mice does not impair antibody-mediated arthritis. J. Exp. Med. 2007, 204:2797-2802.
13. Hayashi S., et al. Exon skipping by mutation of an authentic splice site of c-kit gene in W/W mouse. Nucleic Acids Res. 1991, 19:1267-1271.
14. 41 and W. EMBO J. 1990, 9:1805-1813.
15. sh mutation on mouse chromosome 5 is associated with an inversion. Hum. Mol. Genet. 1995, 4:2073-2079.
16. sh mice interrupts corin and manifests as hematopoietic and cardiac aberrancy. Am. J. Pathol. 2008, 173:1693-1701.
17. Tsai M., et al. Using mast cell knock-in mice to analyze the roles of mast cells in allergic responses in vivo. Chem. Immunol. Allergy 2005, 87:179-197.
18. v. J. Cell. Physiol. 1969, 73:25-30.
19. Feyerabend T.B., et al. Cre-mediated cell ablation contests mast cell contribution in models of antibody- and T cell-mediated autoimmunity. Immunity 2011, 35:832-844.
20. Lantz C.S., et al. Role for interleukin-3 in mast-cell and basophil development and in immunity to parasites. Nature 1998, 392:90-93.
21. v mice. Evidence that cultured mast cells can give rise to both connective tissue type and mucosal mast cells. J. Exp. Med. 1985, 162:1025-1043.
22. Martin T.R., et al. Mast cell activation enhances airway responsiveness to methacholine in the mouse. J. Clin. Invest. 1993, 91:1176-1182.
23. Tanzola M.B., et al. Mast cells exert effects outside the central nervous system to influence experimental allergic encephalomyelitis disease course. J. Immunol. 2003, 171:4385-4391.
24. W-sh sash mice. Clin. Exp. Allergy 2005, 35:82-88.
25. v mice that are genetically deficient in mast cells. J. Exp. Med. 1987, 165:615-627.
26. Scholten J., et al. Mast cell-specific Cre/loxP-mediated recombination in vivo. Transgenic Res. 2008, 17:307-315.
27. Feyerabend T.B., et al. Deletion of Notch1 converts pro-T cells to dendritic cells and promotes thymic B cells by cell-extrinsic and cell-intrinsic mechanisms. Immunity 2009, 30:67-79.
28. fl/fl mice. Blood 2011, 118:6930-6938.
29. Müsch W., et al. Generation and characterization of alpha-chymase-Cre transgenic mice. Genesis 2008, 46:163-166.
30. Dudeck A., et al. Mast cells are key promoters of contact allergy that mediate the adjuvant effects of haptens. Immunity 2011, 34:973-984.
31. Voehringer D., et al. Homeostasis and effector function of lymphopenia-induced "memory-like" T cells in constitutively T cell-depleted mice. J. Immunol. 2008, 180:4742-4753.
32. d genetically mast cell-deficient mice. Blood 1990, 75:1637-1645.
33. d mice acquire anaphylactic responsiveness, but the congenic normal mice do not exhibit augmented responses. J. Clin. Invest. 1993, 92:1639-1649.
34. Schmidt-Supprian M., Rajewsky K. Vagaries of conditional gene targeting. Nat. Immunol. 2007, 8:665-668.
35. Serafin W.E., et al. Carboxypeptidase A in mouse mast cells. Identification, characterization, and use as a differentiation marker. J. Immunol. 1987, 139:3771-3776.
36. Voehringer D., et al. Type 2 immunity reflects orchestrated recruitment of cells committed to IL-4 production. Immunity 2004, 20:267-277.
37. Taghon T., et al. Mast cell lineage diversion of T lineage precursors by the essential T cell transcription factor GATA-3. Nat. Immunol. 2007, 8:845-855.
38. Franco C.B., et al. Distinguishing mast cell and granulocyte differentiation at the single-cell level. Cell Stem Cell 2010, 6:361-368.
39. Steimer D.A., et al. Selective roles for antiapoptotic MCL-1 during granulocyte development and macrophage effector function. Blood 2009, 113:2805-2815.
40. Zhou P., et al. Mcl-1 in transgenic mice promotes survival in a spectrum of hematopoietic cell types and immortalization in the myeloid lineage. Blood 1998, 92:3226-3239.
41. 125I-fibrin deposition in IgE-dependent immediate hypersensitivity reactions in mouse skin. Demonstration of the role of mast cells using genetically mast cell-deficient mice locally reconstituted with cultured mast cells. J. Immunol. 1987, 139:2605-2614.
42. Takeishi T., et al. Differences in the expression of the cardiopulmonary alterations associated with anti-immunoglobulin E-induced or active anaphylaxis in mast cell-deficient and normal mice. Mast cells are not required for the cardiopulmonary changes associated with certain fatal anaphylactic responses. J. Clin. Invest. 1991, 88:598-608.
43. 1-dependent passive anaphylaxis. J. Clin. Invest. 1997, 99:901-914.
44. Mukai K., et al. Basophils play a critical role in the development of IgE-mediated chronic allergic inflammation independently of T cells and mast cells. Immunity 2005, 23:191-202.
45. Newlands G.F., et al. Stem cell factor contributes to intestinal mucosal mast cell hyperplasia in rats infected with Nippostrongylus brasiliensis or Trichinella spiralis, but anti-stem cell factor treatment decreases parasite egg production during N. brasiliensis infection. Blood 1995, 86:1968-1976.
46. Brandt E.B., et al. Mast cells are required for experimental oral allergen-induced diarrhea. J. Clin. Invest. 2003, 112:1666-1677.
47. Gekara N.O., Weiss S. Mast cells initiate early anti-Listeria host defences. Cell. Microbiol. 2008, 10:225-236.
48. Czechowicz A., et al. Efficient transplantation via antibody-based clearance of hematopoietic stem cell niches. Science 2007, 318:1296-1299.
49. Buch T., et al. A Cre-inducible diphtheria toxin receptor mediates cell lineage ablation after toxin administration. Nat. Methods 2005, 2:419-426.
50. Sawaguchi M., et al. Role of mast cells and basophils in IgE responses and in allergic airway hyperresponsiveness. J. Immunol. 2012, 188:1809-1818.
51. Otsuka A., et al. Requirement of interaction between mast cells and skin dendritic cells to establish contact hypersensitivity. PLoS ONE 2011, 6:e25538.
52. Yagi R., et al. Regulation of the Il4 gene is independently controlled by proximal and distal 3' enhancers in mast cells and basophils. Mol. Cell. Biol. 2007, 27:8087-8097.
53. Furumoto Y., et al. PTEN deficiency in mast cells causes a mastocytosis-like proliferative disease that heightens allergic responses and vascular permeability. Blood 2011, 118:5466-5475.
54. Gerbaulet A., et al. Mast cell hyperplasia, B-cell malignancy, and intestinal inflammation in mice with conditional expression of a constitutively active kit. Blood 2011, 117:2012-2021.
55. Sharma N., et al. SH2 domain-containing phosphatase 2 is a critical regulator of connective tissue mast cell survival and homeostasis in mice. Mol. Cell. Biol. 2012, 32:2653-2663.
56. Muzumdar M.D., et al. A global double-fluorescent Cre reporter mouse. Genesis 2007, 45:593-605.
57. Haff L.A. Improved quantitative PCR using nested primers. PCR Methods Appl. 1994, 3:332-337.
58. Galli S.J., Hammel I. Unequivocal delayed hypersensitivity in mast cell-deficient and beige mice. Science 1984, 226:710-713.
59. Bryce P.J., et al. Immune sensitization in the skin is enhanced by antigen-independent effects of IgE. Immunity 2004, 20:381-392.
60. Brown M.A., Hatfield J.K. Mast cells are important modifiers of autoimmune disease: With so much evidence, why is there still controversy?. Front. Immunol. 2012, 3:147.
61. Rodewald H.R., Feyerabend T.B. Widespread immunological functions of mast cells: fact or fiction?. Immunity 2012, 37:13-24.
62. Akahoshi M., et al. Mast cell chymase reduces the toxicity of Gila monster venom, scorpion venom, and vasoactive intestinal polypeptide in mice. J. Clin. Invest. 2011, 121:4180-4191.
63. Gilfillan A.M., Beaven M.A. Regulation of mast cell responses in health and disease. Crit. Rev. Immunol. 2011, 31:475-529.
64. Ribatti D., Crivellato E. Mast cells, angiogenesis and cancer. Adv. Exp. Med. Biol. 2011, 716:270-288.
65. Kennelly R., et al. Mast cells in tissue healing: from skin to the gastrointestinal tract. Curr. Pharm. Des. 2011, 17:3772-3775.
66. Galli S.J., et al. Immunomodulatory mast cells: negative, as well as positive, regulators of immunity. Nat. Rev. Immunol. 2008, 8:478-486.
67. Galli S.J., Tsai M. IgE and mast cells in allergic disease. Nat. Med. 2012, 18:693-704.
68. Abraham S.N., St John A.L. Mast cell-orchestrated immunity to pathogens. Nat. Rev. Immunol. 2010, 10:440-452.
69. Supajatura V., et al. Differential responses of mast cell Toll-like receptors 2 and 4 in allergy and innate immunity. J. Clin. Invest. 2002, 109:1351-1359.
70. Schneider L.A., et al. Molecular mechanism of mast cell mediated innate defense against endothelin and snake venom sarafotoxin. J. Exp. Med. 2007, 204:2629-2639.
71. Metz M., et al. Mast cells can enhance resistance to snake and honeybee venoms. Science 2006, 313:526-530.
72. Enoksson M., et al. Mast cells as sensors of cell injury through IL-33 recognition. J. Immunol. 2011, 186:2523-2528.
73. Lunderius-Andersson C., et al. Mast cells respond to cell injury through the recognition of IL-33. Front. Immunol. 2012, 3:82.
74. Schäfer, B. et al. Mast cell anaphylatoxin receptor expression can enhance IgE-dependent skin inflammation in mice. J. Allergy Clin. Immunol. (in press).
75. Fantozzi R., et al. Mast cell and neutrophil interactions: a role for superoxide anion and histamine. Agents Actions 1985, 16:260-264.
76. Gri G., et al. CD4+CD25+ regulatory T cells suppress mast cell degranulation and allergic responses through OX40-OX40L interaction. Immunity 2008, 29:771-781.
77. Gaudenzio N., et al. Cell-cell cooperation at the T helper cell/mast cell immunological synapse. Blood 2009, 114:4979-4988.
78. Hill P.B., et al. Stem cell factor enhances immunoglobulin E-dependent mediator release from cultured rat bone marrow-derived mast cells: activation of previously unresponsive cells demonstrated by a novel ELISPOT assay. Immunology 1996, 87:326-333.
79. Ito T., et al. Stem cell factor programs the mast cell activation phenotype. J. Immunol. 2012, 188:5428-5437.
80. Galli S.J., et al. The kit ligand, stem cell factor. Adv. Immunol. 1994, 55:1-96.
81. Komai-Koma M., et al. Interleukin-33 amplifies IgE synthesis and triggers mast cell degranulation via interleukin-4 in naive mice. Allergy 2012, 67:1118-1126.
82. Okayama Y., et al. Expression of a functional high-affinity IgG receptor, FcγRI, on human mast cells: up-regulation by IFN-γ. J. Immunol. 2000, 164:4332-4339.
83. Baccari G.C., et al. Mast cells in nonmammalian vertebrates: an overview. Int. Rev. Cell Mol. Biol. 2011, 290:1-53.
84. Galli S.J., et al. Phenotypic and functional plasticity of cells of innate immunity: macrophages, mast cells and neutrophils. Nat. Immunol. 2011, 12:1035-1044.
85. Bowie M.B., et al. Steel factor responsiveness regulates the high self-renewal phenotype of fetal hematopoietic stem cells. Blood 2007, 109:5043-5048.
86. Ikuta K., Weissman I.L. Evidence that hematopoietic stem cells express mouse c-kit but do not depend on steel factor for their generation. Proc. Natl. Acad. Sci. U.S.A. 1992, 89:1502-1506.
87. Ogawa M., et al. Expression and function of c-kit in hemopoietic progenitor cells. J. Exp. Med. 1991, 174:63-71.
88. Galli S.J., et al. Regulation of mouse and human mast cell development, survival and function by stem cell factor, the ligand for the c-kit receptor. Int. Arch. Allergy Immunol. 1995, 107:51-53.
89. Okayama Y., Kawakami T. Development, migration, and survival of mast cells. Immunol. Res. 2006, 34:97-115.
90. Tsai M., et al. Induction of mast cell proliferation, maturation, and heparin synthesis by the rat c-kit ligand, stem cell factor. Proc. Natl. Acad. Sci. U.S.A. 1991, 88:6382-6386.
91. Tsai M., et al. The rat c-kit ligand, stem cell factor, induces the development of connective tissue-type and mucosal mast cells in vivo. Analysis by anatomical distribution, histochemistry, and protease phenotype. J. Exp. Med. 1991, 174:125-131.
92. Oliveira S.H., et al. Stem cell factor induces eosinophil activation and degranulation: mediator release and gene array analysis. Blood 2002, 100:4291-4297.
93. Krishnamoorthy N., et al. Activation of c-Kit in dendritic cells regulates T helper cell differentiation and allergic asthma. Nat. Med. 2008, 14:565-573.
94. Heinemann A., et al. Stem cell factor stimulates the chemotaxis, integrin upregulation, and survival of human basophils. J. Allergy Clin. Immunol. 2005, 116:820-826.
95. Manova K., et al. Gonadal expression of c-kit encoded at the W locus of the mouse. Development 1990, 110:1057-1069.
96. Manova K., Bachvarova R.F. Expression of c-kit encoded at the W locus of mice in developing embryonic germ cells and presumptive melanoblasts. Dev. Biol. 1991, 146:312-324.
97. Huizinga J.D., et al. W/kit gene required for interstitial cells of Cajal and for intestinal pacemaker activity. Nature 1995, 373:347-349.
98. Milenkovic N., et al. Nociceptive tuning by stem cell factor/c-Kit signaling. Neuron 2007, 56:893-906.
99. Takagi K., et al. Involvement of stem cell factor and its receptor tyrosine kinase c-kit in pain regulation. Neuroscience 2008, 153:1278-1288.
100. Peters E.M., et al. KIT is expressed by epithelial cells in vivo. J. Invest. Dermatol. 2003, 121:976-984.
101. Stokman G., et al. Stem cell factor expression after renal ischemia promotes tubular epithelial survival. PLoS ONE 2010, 5:e14386.
102. Cozzi E., et al. The naive airway hyperresponsiveness of the A/J mouse is KIT-mediated. Proc. Natl. Acad. Sci. U.S.A. 2011, 108:12787-12792.
103. Wiener Z., et al. Highly reduced peritoneal mast cell number and decreased c-kit expression in histidine decarboxylase knock out mice. Inflamm. Res. 2001, 50(Suppl. 2):S55-S56.
104. Ohtsu H., et al. Mice lacking histidine decarboxylase exhibit abnormal mast cells. FEBS Lett. 2001, 502:53-56.
105. Wastling J.M., et al. Histochemical and ultrastructural modification of mucosal mast cell granules in parasitized mice lacking the β-chymase, mouse mast cell protease-1. Am. J. Pathol. 1998, 153:491-504.
106. Younan G., et al. The inflammatory response after an epidermal burn depends on the activities of mouse mast cell proteases 4 and 5. J. Immunol. 2010, 185:7681-7690.
107. Tchougounova E., et al. The chymase, mouse mast cell protease 4, constitutes the major chymotrypsin-like activity in peritoneum and ear tissue. A role for mouse mast cell protease 4 in thrombin regulation and fibronectin turnover. J. Exp. Med. 2003, 198:423-431.
108. Stevens R.L., et al. Transgenic mice that possess a disrupted mast cell protease 5 (mMCP-5) gene can not store carboxypeptidase A (mMC-CPA) protein in their granules. FASEB J. 1996, 10:17772.
109. Abonia J.P., et al. Mast cell protease 5 mediates ischemia-reperfusion injury of mouse skeletal muscle. J. Immunol. 2005, 174:7285-7291.
110. Thakurdas S.M., et al. The mast cell-restricted tryptase mMCP-6 has a critical immunoprotective role in bacterial infections. J. Biol. Chem. 2007, 282:20809-20815.
111. Shin K., et al. Mouse mast cell tryptase mMCP-6 is a critical link between adaptive and innate immunity in the chronic phase of trichinella spiralis infection. J. Immunol. 2008, 180:4885-4891.
112. Hunt J.E., et al. Natural disruption of the mouse mast cell protease 7 gene in the C57BL/6 mouse. J. Biol. Chem. 1996, 271:2851-2855.
113. Feyerabend T.B., et al. Loss of histochemical identity in mast cells lacking carboxypeptidase A. Mol. Cell. Biol. 2005, 25:6199-6210.
114. Humphries D.E., et al. Heparin is essential for the storage of specific granule proteases in mast cells. Nature 1999, 400:769-772.
115. Forsberg E., et al. Abnormal mast cells in mice deficient in a heparin-synthesizing enzyme. Nature 1999, 400:773-776.
116. Kung T.T., et al. Mast cells modulate allergic pulmonary eosinophilia in mice. Am. J. Respir. Cell Mol. Biol. 1995, 12:404-409.
117. Takeda K., et al. Development of eosinophilic airway inflammation and airway hyperresponsiveness in mast cell-deficient mice. J. Exp. Med. 1997, 186:449-454.
118. Kobayashi T., et al. An essential role of mast cells in the development of airway hyperresponsiveness in a murine asthma model. J. Immunol. 2000, 164:3855-3861.
119. Williams C.M., Galli S.J. Mast cells can amplify airway reactivity and features of chronic inflammation in an asthma model in mice. J. Exp. Med. 2000, 192:455-462.
120. Yu M., et al. Mast cells can promote the development of multiple features of chronic asthma in mice. J. Clin. Invest. 2006, 116:1633-1641.
121. H2 cytokine production in an asthma model in mice. J. Allergy Clin. Immunol. 2007, 120:48-55.
122. Becker M., et al. Genetic variation determines mast cell functions in experimental asthma. J. Immunol. 2011, 186:7225-7231.
123. Lee D.M., et al. Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 2002, 297:1689-1692.
124. Elliott E.R., et al. Deletion of Syk in neutrophils prevents immune complex arthritis. J. Immunol. 2011, 187:4319-4330.
125. Mancardi D.A., et al. Cutting edge: the murine high-affinity IgG receptor FcγRIV is sufficient for autoantibody-induced arthritis. J. Immunol. 2011, 186:1899-1903.
126. Secor V.H., et al. Mast cells are essential for early onset and severe disease in a murine model of multiple sclerosis. J. Exp. Med. 2000, 191:813-822.
127. Bennett J.L., et al. Bone marrow-derived mast cells accumulate in the central nervous system during inflammation but are dispensable for experimental autoimmune encephalomyelitis pathogenesis. J. Immunol. 2009, 182:5507-5514.
128. (W-sh) mice develop earlier and more severe experimental autoimmune encephalomyelitis due to absence of immune suppression. J. Immunol. 2011, 187:274-282.
129. W-sh/W-sh mice. Lab. Invest. 2011, 91:627-641.
130. d mast cell-deficient mice. J. Immunol. 1983, 131:2687-2694.
131. Biedermann T., et al. Mast cells control neutrophil recruitment during T cell-mediated delayed-type hypersensitivity reactions through tumor necrosis factor and macrophage inflammatory protein 2. J. Exp. Med. 2000, 192:1441-1452.
132. Norman M.U., et al. Mast cells regulate the magnitude and the cytokine microenvironment of the contact hypersensitivity response. Am. J. Pathol. 2008, 172:1638-1649.
133. Abt M.C., Artis D. The intestinal microbiota in health and disease: the influence of microbial products on immune cell homeostasis. Curr. Opin. Gastroenterol. 2009, 25:496-502.
134. Abt M.C., et al. Commensal bacteria calibrate the activation threshold of innate antiviral immunity. Immunity 2012, 37:158-170.
135. Hill D.A., et al. Commensal bacteria-derived signals regulate basophil hematopoiesis and allergic inflammation. Nat. Med. 2012, 18:538-546.
136. Finkelman F.D. Anaphylaxis: lessons from mouse models. J. Allergy Clin. Immunol. 2007, 120:506-517.
137. Nigrovic P.A., Lee D.M. Synovial mast cells: role in acute and chronic arthritis. Immunol. Rev. 2007, 217:19-37.
138. d mice. J. Immunol. 1985, 135:879-885.
139. Mekori Y.A., et al. Studies of the role of mast cells in contact sensitivity responses. Passive transfer of the reaction into mast cell-deficient mice locally reconstituted with cultured mast cells: effect of reserpine on transfer of the reaction with DNP-specific cloned T cells. Cell. Immunol. 1987, 109:39-52.
140. Yu M., et al. Identification of an IFN-γ/mast cell axis in a mouse model of chronic asthma. J. Clin. Invest. 2011, 121:3133-3143.