Lineage-specific regulation of allergic airway inflammation by the lipid phosphatase Src homology 2 domain-containing inositol 5-phosphatase (SHIP-1).
BACKGROUND
Inpp5d (Src homology 2 domain-containing inositol-5-phosphatase [Ship1])-deficient mice experience spontaneous airway inflammation and have enhanced sensitivity to allergen-induced airway inflammation.


OBJECTIVE
We hypothesized that lineage-specific deletion of Ship1 expression in cells known to be crucial for adaptive TH2 responses would uncover distinct roles that could either positively or negatively regulate susceptibility to allergic airway inflammation (AAI).


METHODS
Ship1 expression was deleted in B cells, T cells, or dendritic cells (DCs), and the resulting Ship1(ΔB cell), Ship1(ΔT cell), Ship1(ΔDC), or Ship1(F/F) (wild-type) control mice were evaluated in a model of house dust mite (HDM)-induced AAI.


RESULTS
Unlike germline panhematopoietic Ship1 deletion, deletion of Ship1 selectively in either the B-cell, T-cell, or DC lineages did not result in spontaneous airway inflammation. Strikingly, although loss of Ship1 in the B-cell lineage did not affect HDM-induced AAI, loss of Ship1 in either of the T-cell or DC lineages protected mice from AAI by skewing the typical TH2 immune response toward a TH1 response.


CONCLUSIONS
Although panhematopoietic deletion of Ship1 leads to spontaneous lung inflammation, selective deletion of Ship1 in T cells or DCs impairs the formation of an adaptive TH2 response and protects animals from HDM-induced AAI.
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Matthew J
MJ
Gold
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Michael R
MR
Hughes
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.
Frann
F
Antignano
UBC James Hogg Research Centre, St Paul's Hospital, Vancouver, British Columbia, Canada.
Jeremy A
JA
Hirota
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Department of Biochemistry and Molecular Biology, Monash University, Clayton, Australia.
Colby
C
Zaph
The Biomedical Research Centre, University of British Columbia, Vancouver, British Columbia, Canada. Electronic address: kelly@brc.ubc.ca.
Kelly M
KM
McNagny
D056704:Adaptive Immunity; D000485:Allergens / Q000008:administration & dosage / Q000276:immunology; D000818:Animals; D039741:Antigens, Dermatophagoides / Q000008:administration & dosage / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology; D016535:Bronchial Hyperreactivity / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D019070:Cell Lineage / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000473:pathology; D015870:Gene Expression; D000072181:Inositol Polyphosphate 5-Phosphatases; D051379:Mice; D018345:Mice, Knockout; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000172:deficiency / Q000235:genetics / Q000276:immunology*; D011014:Pneumonia / Q000139:chemically induced / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D039981:Pyroglyphidae / Q000737:chemistry; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D058408:Th1-Th2 Balance
D000485:Allergens; D039741:Antigens, Dermatophagoides; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases
Allergy; IgE; T(H)2; asthma; dendritic cell; house dust mite