Coordinated involvement of mast cells and T cells in allergic mucosal inflammation: critical role of the CC chemokine ligand 1:CCR8 axis.
CCL1 is the predominant chemokine secreted from IgE-activated human and mouse mast cells in vitro, colocalizes to mast cells in lung biopsies, and is elevated in asthmatic airways. CCR8, the receptor for CCL1, is expressed by approximately 70% of CD4(+) T lymphocytes recruited to the asthmatic airways, and the number of CCR8-expressing cells is increased 3-fold in the airways of asthmatic subjects compared with normal volunteers. In vivo, CCL1 expression in the lung is reduced in mast cell-deficient mice after aeroallergen provocation. Neutralization of CCL1 or CCR8 deficiency results in reduced mucosal lung inflammation, airway hyperresponsiveness, and mucus hypersecretion to a similar degree as detected in mast cell-deficient mice. Adenoviral delivery of CCL1 to the lungs of mast cell-deficient mice restores airway hyperresponsiveness, lung inflammation, and mucus hypersecretion to the degree observed in wild-type mice. The consequences of CCR8 deficiency, including a marked reduction in Th2 cytokine levels, are comparable with those observed by depletion of CD4(+) T lymphocytes. Thus, mast cell-derived CCL1- and CCR8-expressing CD4(+) effector T lymphocytes play an essential role in orchestrating lung mucosal inflammatory responses.
Gonzalo
Jose-Angel
JA
Department of Mucosal Immunology and Pharmacology, Millennium Pharmaceuticals, Inc., Cambridge, MA 02139, USA.
Qiu
Yubin
Y
Lora
Jose M
JM
Al-Garawi
Amal
A
Villeval
Jean-Luc
JL
Boyce
Joshua A
JA
Martinez-A
Carlos
C
Marquez
Gabriel
G
Goya
Iñigo
I
Hamid
Qutayba
Q
Fraser
Christopher C
CC
Picarella
Dominic
D
Cote-Sierra
Javier
J
Hodge
Martin R
MR
Gutierrez-Ramos
Jose-Carlos
JC
Kolbeck
Roland
R
Coyle
Anthony J
AJ
D000818:Animals; D001249:Asthma / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D054402:Chemokine CCL1; D019742:Chemokines, CC / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D006801:Humans; D006967:Hypersensitivity / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D007073:Immunoglobulin E / Q000494:pharmacology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008407:Mast Cells / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051381:Rats; D011921:Rats, Inbred WKY; D054401:Receptors, CCR8; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D020545:Respiratory Mucosa / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
C502258:Ccl1 protein, mouse; C489319:Ccr8 protein, mouse; D054402:Chemokine CCL1; D019742:Chemokines, CC; D016207:Cytokines; D054401:Receptors, CCR8; D019707:Receptors, Chemokine; D007073:Immunoglobulin E