A novel function of ADP-ribosyl cyclases to regulate the length of the small intestine revealed in CD38/CD157 double knockout mice

Abstract

Abstract Mammalian ADP-ribosyl cyclase includes two ectoenzymes; GPI-anchored, Bone marrow stromal cell antigen-1 (BST-1)/CD157 and a type II membrane protein, CD38. Although they are expressed in various tissues including the lung, kidney, intestine, brain, spleen and bone marrow, the enzymatic activity of CD38 is dominant at physiological pH. We generated and analyzed CD157 deficient mice (CD157KO), and reported that CD157 is a positive regulator of humoral immunity in 129 x C57BL/6J (B6) mixed background. Recently, various groups reported novel functions of murine CD157 in intestinal regeneration and depressive or anxious behaviors. Thus, CD157 is now appreciated as an entero-neuro-immune regulator. The phenotypes of CD38KO also revealed the multiple functions of CD38 in immunity, metabolism, social behaviors, as well as in the kidney and lung. To further clarify the function of ADP-ribosyl cyclase family, we generated CD38/CD157 doubly deficient mice (CD38/157DKO) by sequential targeting at ES cell level, and compared with CD38KO, CD157KO and wild type in B6 background. A novel phenotype unique to B6.CD157KO was enhanced humoral immune responses to TNP-LPS, indicating the suppressive role of CD157 in TLR signal on marginal zone B cell. Although CD38/157DKO developed apparently normal with no histological changes in the major tissues by HE staining, the length of the small intestine increased by approximately 20% at 4 months old. Among the lymphoid organs, the cell numbers in the mesenteric lymph node increased by 1.5 times without changes in the lineage or subset, probably reflecting elongation of the small intestine. These data suggest that ADP-ribosyl cyclases, CD38 and CD157, have roles in regulating functions of the small intestine.