Thymic stromal lymphopoietin contributes to myeloid hyperplasia and increased immunoglobulins, but not epidermal hyperplasia, in RabGEF1-deficient mice.
Mice overexpressing the proallergic cytokine thymic stromal lymphopoietin (TSLP) in the skin develop a pathology resembling atopic dermatitis. RabGEF1, a guanine nucleotide exchange factor for Rab5 GTPase, is a negative regulator of IgE-dependent mast cell activation, and Rabgef1-/- and TSLP transgenic mice share many similar phenotypic characteristics, including elevated serum IgE levels and severe skin inflammation, with infiltrates of both lymphocytes and eosinophils. We report here that Rabgef1-/- mice also develop splenomegaly, lymphadenopathy, myeloid hyperplasia, and high levels of TSLP. Rabgef1-/-TSLPR-/- mice, which lack TSLP/TSLP receptor (TSLPR) signaling, had levels of blood neutrophils, spleen myeloid cells, and serum IL-4, IgG1, and IgE levels that were significantly reduced compared with those in Rabgef1-/-TSLPR+/+ mice. However, Rabgef1-/-TSLPR-/- mice, like Rag1- or eosinophil-deficient Rabgef1-/- mice, developed cutaneous inflammation and epidermal hyperplasia. Therefore, in Rabgef1-/- mice, TSLP/TSLPR interactions are not required for the development of epidermal hyperplasia but contribute to the striking myeloid hyperplasia and overproduction of immunoglobulins observed in these animals. Our study shows that RabGEF1 can negatively regulate TSLP production in vivo and that excessive production of TSLP contributes to many of the phenotypic abnormalities in Rabgef1-/- mice. However, the marked epidermal hyperplasia, cutaneous inflammation, and increased numbers of dermal mast cells associated with RabGEF1 deficiency can develop via a TSLPR-independent pathway, as well as in the absence of Rag1 or eosinophils.
Tsai
Mindy
M
Stanford University School of Medicine, Department of Pathology, L-235, 300 Pasteur Drive, Stanford, CA 94305-5324, USA. mindyt@stanford.edu
Chen
Ching-Cheng
CC
Mukai
Kaori
K
Song
Chang Ho
CH
Thompson
Lucas J
LJ
Ziegler
Steven F
SF
Tam
See-Ying
SY
Galli
Stephen J
SJ
D056704:Adaptive Immunity; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D016207:Cytokines / Q000097:blood / Q000276:immunology*; D004817:Epidermis / Q000276:immunology / Q000473:pathology*; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D006965:Hyperplasia; D007136:Immunoglobulins / Q000097:blood / Q000276:immunology*; D015847:Interleukin-4 / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology*; D010641:Phenotype; D018121:Receptors, Cytokine / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D000094632:Thymic Stromal Lymphopoietin
D016207:Cytokines; D020662:Guanine Nucleotide Exchange Factors; D007136:Immunoglobulins; C510870:RabGEF1 protein, mouse; D018121:Receptors, Cytokine; C410591:Tslpr protein, mouse; D015847:Interleukin-4; D000094632:Thymic Stromal Lymphopoietin; C000721967:TSLP protein, mouse