Local Complement production and TLR crosstalk in intestinal ischemia/reperfusion

Abstract

Abstract Intestinal ischemia/reperfusion (IR)-induced tissue damage requires crosstalk between complement components and toll-like receptors (TLR). TLR2 and TLR4 are expressed on both white blood cells and intestinal epithelial cells. In addition, complement may be produced in the local tissue as well as in the liver. We hypothesized that expression of TLRs would induce local production of complement components by circulating white blood cells and together result in IR-induced injury. To evaluate this hypothesis, we created chimeric mice by injecting wildtype bone marrow to lethally irradiated TLR2 or TLR4 deficient mice or TLR deficient bone marrow to lethally irradiated wildtype mice. The chimeric mice were subjected to intestinal IR and injury, production of complement components and TLR-mediated inflammatory products analyzed. IR-induced injury required TLR4 on the intestinal tissue whereas expression of TLR2 on either intestinal or white blood cells was sufficient for injury. In contrast, PGE2 production required TLR expression on bone marrow derived cells. TLR4 expression on non-hematopoietic tissue was sufficient for IR-induced complement C3 deposition. However, C3 was deposited on TLR2 chimeric mice if any type of wildtype cells were present, similar to intestinal injury. Together these data indicate distinct crosstalk between the specific TLRs and C3 during IR-induced injury and inflammation.