Abnormal CX3CR1⁺ lamina propria myeloid cells from intestinal transplant recipients with NOD2 mutations.
Although progress has been made in intestinal transplantation, chronic inflammation remains a challenge. We have reported that the risk of immunological graft loss is almost 100-fold greater in recipients who carry any of the prevalent NOD2 polymorphisms associated with Crohn's disease, and have shown that the normal levels of a key antimicrobial peptide produced by the Paneth cells of the allograft, fall as the graft becomes repopulated by hematopoietic cells of the NOD2 mutant recipient. These studies are extended in this report. Within several months following engraftment into a NOD2 mutant recipient the allograft loses its capacity to prevent adherence of lumenal microbes. Despite the significantly increased expression of CX3CL1, a stress protein produced by the injured enterocyte, NOD2 mutant CX3CR1(+)  myeloid cells within the lamina propria fail to exhibit the characteristic morphological phenotype, and fail to express key genes required expressed by NOD2 wild-type cells, including Wnt 5a. We propose that the CX3CR1(+)  myeloid cell within the lamina propria supports normal Paneth cell function through expression of Wnt 5a, and that this function is impaired in the setting of intestinal transplantation into a NOD2 mutant recipient. The therapeutic value of Wnt 5a administration in this setting is proposed.
Department of Surgery, Transplant Institute, Georgetown University Medical Center, Washington, DC, USA.
D
D
Lough
J
J
Abdo
J F
JF
Guerra-Castro
C
C
Matsumoto
S
S
Kaufman
K
K
Shetty
Y K
YK
Kwon
M
M
Zasloff
T M
TM
Fishbein
D000293:Adolescent; D000328:Adult; D015153:Blotting, Western; D000073883:CX3C Chemokine Receptor 1; D002648:Child; D002675:Child, Preschool; D003424:Crohn Disease / Q000150:complications / Q000235:genetics*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005455:Fluorescent Antibody Technique; D005838:Genotype; D006801:Humans; D007124:Immunoenzyme Techniques; D007223:Infant; D007415:Intestinal Obstruction / Q000150:complications / Q000235:genetics / Q000601:surgery; D007422:Intestines / Q000637:transplantation*; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane / Q000378:metabolism / Q000473:pathology*; D009154:Mutation / Q000235:genetics*; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics*; D019879:Paneth Cells / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011183:Postoperative Complications; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D019707:Receptors, Chemokine / Q000235:genetics / Q000378:metabolism*; D012307:Risk Factors; D014184:Transplantation, Homologous; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; D055815:Young Adult
D000073883:CX3C Chemokine Receptor 1; C095235:CX3CR1 protein, human; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D019707:Receptors, Chemokine; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein