Investigation of the effect of bdnf on NLRP3 inflammasome and NLRP3 mediated pyroptosis

Inflammasomes are multiprotein complexes that are activated by various stimuli such as pathogen-associated molecular patterns (PAMP) or damage-associated molecular patterns (DAMP) and play an important role in the innate immune response. When the NOD-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome is activated, cytokines such as interleukin-1β (IL-1β) and interleukin-18 (IL-18) are released via caspase-1. Since cell death also occurs when the NLRP3 inflammasome is activated, regulation and inhibition of inflammasome activation may be a useful way to treat and prevent inflammation-related diseases. Therefore, immunomodulatory therapeutic endogenous molecules are highly needed to reduce inflammation. Brain-derived neurotrophic factor (BDNF), a neurotrophin with immunomodulatory effects, is an attractive candidate for suppressing excessive inflammation. However, how BDNF affects the NLRP3 inflammasome and pyroptosis, a type of inflammatory cell death caused by the NLRP3 inflammasome, has not yet been investigated. In this study, it was aimed to examine the effect of BDNF on NLRP3 inflammasome activation, gasdermin D (GSDMD)-mediated pyroptotic cell death, and negative regulators of this pathway. In the in vivo model, NLRP3 inflammasome activation was achieved by applying lipopolysaccharide (LPS) and nigericin (Nig) in Bdnf (+/+) and Bdnf (+/-) mice. At the end of NLRP3 inflammasome activation, the levels of BDNF, IL-1β and IL-18 in serum samples were determined by ELISA method, and the levels of proteins related to the NLRP3 inflammasome pathway and negative regulators of this pathway in hippocampus, cortex, liver, epididymal adipose and muscle tissue samples were determined by Western blot method. It was revealed that BDNF deficiency increased the levels of NLRP3 inflammasome-related proteins through the activation of nuclear factor kappa B (NF-κB), stimulated the release of IL-1β and IL-18 and pyroptotic cell death. Additionally, BDNF deficiency was shown to inhibit autophagy, autophagosome formation, and plasma membrane repair, which are important pathways in the inhibition of NLRP3 inflammasome activation and pyroptosis. As a result, BDNF deficiency causes increased inflammasome activation and GSDMD-mediated pyroptosis.