TLR2 initiates intestinal ischemia/reperfusion induced tissue damage (P4003)

Abstract

Abstract Reperfusion (the return of blood flow) significantly magnifies ischemia (lack of blood flow) induced tissue damage in multiple clinical conditions including trauma and hemorrhage. During reperfusion, naturally occurring antibodies recognize endogenous damage-associated molecular patterns (DAMP), followed by an excessive complement activation, neutrophil infiltration and inflammatory response which frequently results in an excessive systemic inflammatory response which may lead to death. TLRs recognize DAMP and TLR4 is required for intestinal ischemia-reperfusion (IR). As TLR2 has been proposed to be the receptor for at least one DAMP, the serum protein, β2-glycoprotein I (β2-GPI) which is critical in intestinal ischemia reperfusion (IR), we hypothesized that IR-induced intestinal damage requires TLR2 for subsequent inflammation and tissue damage. Using TLR2-/- mice, we demonstrate that TLR2 is required for excessive IR-induced complement activation and pro-inflammatory cytokine production. TLR2-/- mice not only lacked the appropriate antibody repertoire to induce intestinal IR but treatment with wildtype antibodies was not sufficient to induce tissue damage or inflammation. Compared to wildtype mice, TLR2-/- mice have increased serum β2-GPI but β2-GPI is not deposited on ischemic intestinal tissue. Our data suggest that TLR2 interacts with β2-GPI and is required for neo-antigen expression and initiation of the systemic inflammatory response during intestinal IR.