Der Toll-like Rezeptor-TRIF Signaltransduktionsweg in der akuten Pankreatitis

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Acute pancreatitis (AP) is a potentially lethal disease often involving peripancreatic tissues and sometimes affecting distant organs. The severity of the disease depends on the extent and type of acinar cell death: while induction of apoptosis ameliorates AP, its inhibition worsens the disease. During AP, detection of endogenous factors (“danger” signals) released from “stressed” cells might be conferred by Toll-like receptors (TLRs) either on acinar cells themselves, on neighboring cells or on immune cells. In a preliminary set of experiments, severity of pancreatitis was strikingly worsened and increased pancreatic tissue necrosis was observed in mice lacking the common signaling adaptor protein of TLR3 and TLR4, the Toll/interleukin-1 receptor domain-containing adaptor protein, TRIF. In this project proposal, we aim at elucidating whether these observed effects are due to a direct TRIF function in acinar cells, are indirectly due to modulation of immune cell responses or both. We propose as a new concept that TRIF functions as a gatekeeper between apoptosis and necrosis in pancreatic acinar cells. Thus, TRIF may control local inflammation during acute pancreatitis and perpetuation of a systemic inflammatory response.