Abstract
Von Willebrand factor (VWF) is secreted as an acute phase protein during inflammation. ADAMTS-13 regulates the size and prothrombotic activity of VWF by it’s specific proteolytic activity. To determine the relevance of this regulatory pathway for the innate inflammatory response by polymorphonuclear neutrophils (PMN), we employed a mouse model of invasive pulmonary aspergillosis (IPA) where PMN functionality is crucial for fungal clearance and survival. IPA was induced by intratracheal application of Aspergillus fumigatus (A. fumigatus) conidia in wildtype (129/Sv/Pas) or ADAMTS-13 deficient (Adamts13−/−) mice. While neutropenic mice developed lethal IPA, all wildtype mice survived the infection. In contrast to wildtype or VWF deficient mice, Adamts13−/− mice displayed more severe signs of disease with a lethal course in 24% with an increased fungal burden and signs of acute lung injury. Histology sections demonstrated a more pronounced perivascular leukocyte infiltration in support of a dysregulated inflammatory response in Adamts13−/− mice. Importantly, we observed no general defect in the activation of neutrophil functions in response to conidia or hyphae in vitro. Therefore, we conclude that the proteolytic regulation of VWF by ADAMTS-13 or ADAMTS-13 by itself is an important mechanism to control PMN recruitment in acute inflammatory processes, such as fungal pneumonias.
Highlights
Von Willebrand factor (VWF) is secreted as an acute phase protein during inflammation
polymorphonuclear neutrophils (PMN) from Adamts13−/− mice were fully functional in terms of the activation of effector mechanisms in response to microbial or fungal stimuli as well as killing of A. fumigatus conidia or hyphae
Since Ultra-large VWF multimers (UL-VWF) multimers have no effect on C3b cleavage and permit default complement activation compared to normal plasma VWF multimers[23], we investigated whether altered serum complement content and the chemotactic ability of serum components is involved in modified PMN migration
Summary
Von Willebrand factor (VWF) is secreted as an acute phase protein during inflammation. We demonstrate that Adamts[13] gene deficient mice (Adamts13−/−) show an increased mortality compared to wildtype mice when challenged with A. fumigatus conidia intratracheally (i.t.). This was associated with a higher fungal load in the lungs and albumin in the bronchoalveolar lavage fluid (BALF) and complement deposition as indicators of more severe tissue damage. PMN from Adamts13−/− mice were fully functional in terms of the activation of effector mechanisms in response to microbial or fungal stimuli as well as killing of A. fumigatus conidia or hyphae. ADAMTS-13 deficiency causes an impaired innate immune response against A. fumigatus infections mediated by a dysregulated inflammatory response and impaired PMN recruitment to the lungs
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