CD44 deficiency attenuates chronic murine ileitis.
OBJECTIVE
Lymphocyte recruitment to sites of inflammation requires the sequential engagement of adhesion molecules and chemokine receptors. In the current studies we analyzed the role of CD44 for the development of chronic small-intestinal inflammatory infiltrates in vivo.


METHODS
By using a tumor necrosis factor (TNF)-driven model of chronic ileitis (ie, B6.129P-TNF(DeltaAU-rich element [ARE])) that recapitulates many features of Crohn's disease, we noticed dynamic changes in the expression and functional state of CD44 and its ligand hyaluronan via enzyme-linked immunosorbent assay, real-time reverse-transcription polymerase chain reaction, immunohistochemistry, and flow cytometry. In addition, we assessed the role of lymphocyte populations during induction of ileitis through adoptive transfer studies, and generated CD44-deficient TNFDeltaARE mice to assess the role of CD44 for development of ileitis.


RESULTS
Soluble hyaluronan levels and expression of hyaluronan synthase-1 were increased in TNFDeltaARE mice. This coincided with increased expression of CD44 (including variant 7) and reactivity towards hyaluronan on CD4(+) T cells. CD44 was spatially colocalized with the gut-homing integrin alpha(4)beta(7), spatially linking lymphocyte rolling with arrest. These cells had an effector phenotype because they lacked L-selectin and a higher proportion in diseased mice produced TNF and interleukin-2 compared with wild-type littermates. Lastly, CD4(+) but not CD8(+) T cells conferred ileitis to RAG(-/-) recipients and deficiency of one or both alleles of the CD44 gene resulted in attenuation of the severity of ileitis in TNFDeltaARE mice.


CONCLUSIONS
Our findings support an important role of CD44 expressed by CD4(+) and CD8(+) for development of ileitis mediated by TNF overproduction.
Mucosal Inflammation Program, Division of Gastroenterology, University of Colorado Health Sciences Center, Denver, Colorado 80206, USA.
Colm B
CB
Collins
Johnson
J
Ho
Theodore E
TE
Wilson
Joshua D
JD
Wermers
José L
JL
Tlaxca
Michael B
MB
Lawrence
Michael
M
Solga
Joanne
J
Lannigan
Jesús
J
Rivera-Nieves
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002908:Chronic Disease; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007079:Ileitis / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D007082:Ileum / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018960:Hyaluronan Receptors; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha