Role of CD44 and its v7 isoform in staphylococcal enterotoxin B-induced toxic shock: CD44 deficiency on hepatic mononuclear cells leads to reduced activation-induced apoptosis that results in increased liver damage.
Exposure to bacterial superantigens such as staphylococcal enterotoxin B (SEB) leads to the induction of toxic shock syndrome which results in multiorgan failure, including liver damage. In the present study, we investigated the role of CD44 in SEB-induced liver injury. Injection of SEB into d-galactosamine-sensitized CD44 wild-type (WT) mice led to a significant increase in CD44 expression on liver T cells, NK cells, and NKT cells. Administration of SEB to CD44 knockout (KO) mice caused significantly enhanced liver damage which correlated with elevated numbers of T cells, NK cells, NKT cells, and macrophages in the liver and increased production of tumor necrosis factor alpha and gamma interferon compared to CD44 WT mice. Furthermore, liver mononuclear cells from CD44 KO mice were resistant to SEB-induced apoptosis, and cDNA microarray analysis revealed that SEB activation of such cells led to the induction of several antiapoptotic genes and repression of proapoptotic genes. Examination of CD44 isoforms revealed that SEB exposure altered CD44 variant 7 (v7) isoform expression. Interestingly, mice bearing a specific deletion of the CD44v7 exon exhibited increased susceptibility to SEB-induced hepatitis. Finally, treatment of CD44 WT mice with anti-CD44 monoclonal antibodies reduced expression of CD44 in liver mononuclear cells and caused increased susceptibility to SEB-induced liver injury. Together, these data demonstrate that the expression of CD44 and/or CD44v7 on SEB-activated liver mononuclear cells facilitates their rapid apoptosis, thereby preventing severe liver injury in wild-type mice, and suggest that CD44 plays an important role in the regulation and elimination of immune cells in the liver.
McKallip
Robert J
RJ
Department of Microbiology and Immunology, Massey Cancer Center, Virginia Commonwealth University Medical Center, Box 980678, Richmond, VA 23298-0678. mnagark@hsc.vcu.edu.
Fisher
Michael
M
Gunthert
Ursula
U
Szakal
Andras K
AK
Nagarkatti
Prakash S
PS
Nagarkatti
Mitzi
M
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D002455:Cell Division; D016207:Cytokines / Q000502:physiology; D004768:Enterotoxins / Q000633:toxicity*; D005260:Female; D006505:Hepatitis / Q000209:etiology; D018960:Hyaluronan Receptors / Q000502:physiology*; D008099:Liver / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012772:Shock, Septic / Q000209:etiology*; D051028:bcl-2-Associated X Protein
C476399:Cd44 protein, mouse; D016207:Cytokines; D004768:Enterotoxins; D018960:Hyaluronan Receptors; D019253:Proto-Oncogene Proteins c-bcl-2; D012333:RNA, Messenger; D051028:bcl-2-Associated X Protein; C031818:enterotoxin B, staphylococcal