NLRP3 Activation Induced by Neutrophil Extracellular Traps Sustains Inflammatory Response in the Diabetic Wound

Persistent inflammatory response in the diabetic wound impairs the healing process, resulting in significant morbidity and mortality. Mounting evidence indicates that the activation of Nod-like receptor protein (NLRP) 3 inflammasome in macrophages (M) contributes to the sustained inflammatory response and impaired wound healing associated with diabetes. However, the main trigger of NLRP3 inflammasome in the wounds is not known. Neutrophils, as sentinels of the innate immune system and key stimulators of M, are immune cells that play the main role in the early phase of healing. Neutrophils release extracellular traps (NETs) as defense against pathogens. On the other hand, NETs induce tissue damage. NETs have been detected in the diabetic wound and implicated in the impaired healing process, but the mechanism of NETs suspend wound healing and its role in fostering inflammatory dysregulation are elusive. Here, we report that NLRP3 and NETs production are elevated in human and rat diabetic wounds. NETs overproduced in the diabetic wounds triggered NLRP3 inflammasome activation and IL-1β release in M. Furthermore, NETs up-regulated NLRP3 and pro-IL-1β levels via the TLR-4/TLR-9/NF-B signalling pathway. They also elicited the generation of reactive oxygen species, which facilitated the association between NLRP3 and TXNIP, and activated the NLRP3 inflammasome. In addition, NET digestion by DNase I alleviated the activation of NLRP3 inflammasome, regulated the immune cell i...
Source: Clinical Science - Category: Biomedical Science Authors: Tags: PublishAheadOfPrint Source Type: research