Renner B, Coleman K, Goldberg R, Amura C, Holland-Neidermyer A, Pierce K, Orth HN, Molina H, Ferreira VP, Cortes C, Pangburn MK, Holers VM, Thurman JM
The complement inhibitors Crry and factor H are critical for preventing autologous complement activation on renal tubular epithelial cells.
J Immunol. 2010 Sep 1;185(5):3086-94
Authors: Renner B, Coleman K, Goldberg R, Amura C, Holland-Neidermyer A, Pierce K, Orth HN, Molina H, Ferreira VP, Cortes C, Pangburn MK, Holers VM, Thurman JM
Congenital and acquired deficiencies of complement regulatory proteins are associated with pathologic complement activation in several renal diseases. To elucidate the mechanisms by which renal tubular epithelial cells (TECs) control the complement system, we examined the expression of complement regulatory proteins by the cells. We found that Crry is the only membrane-bound complement regulator expressed by murine TECs, and its expression is concentrated on the basolateral surface. Consistent with the polarized localization of Crry, less complement activation was observed when the basolateral surface of TECs was exposed to serum than when the apical surface was exposed. Furthermore, greater complement activation occurred when the basolateral surface of TECs from Crry(-/-)fB(-/-) mice was exposed to normal serum compared with TECs from wild-type mice. Complement activation on the apical and basolateral surfaces was also greater when factor H, an alternative pathway regulatory protein found in serum, was blocked from interacting with the cells. Finally, we injected Crry(-/-)fB(-/-) and Crry(+/+)fB(-/-) mice with purified factor B (an essential protein of the alternative pathway). Spontaneous complement activation was seen on the tubules of Crry(-/-)fB(-/-) mice after injection with factor B, and the mice developed acute tubular injury. These studies indicate that factor H and Crry regulate complement activation on the basolateral surface of TECs and that factor H regulates complement activation on the apical surface. However, congenital deficiency of Crry or reduced expression of the protein on the basolateral surface of injured cells permits spontaneous complement activation and tubular injury.
PMID: 20675597 [PubMed - in process]