Peroxidase-Mimicking Nanoassembly Mitigates Lipopolysaccharide-Induced Endotoxemia and Cognitive Damage in the Brain by Impeding Inflammatory Signaling in Macrophages.
Rajendrakumar Santhosh Kalash,Revuri Vishnu,Samidurai Manikandan,Mohapatra Adityanarayan,Lee Jae Hyuk,Ganesan Palanivel,Jo Jihoon,Lee Yong-Kyu,Park In-Kyu
Oxidative stress during sepsis pathogenesis remains the most-important factor creating imbalance and dysregulation in immune-cell function, usually observed following initial infection. Hydrogen peroxide (HO), a potentially toxic reactive oxygen species (ROS), is excessively produced by pro-inflammatory immune cells during the initial phases of sepsis and plays a dominant role in regulating the pathways associated with systemic inflammatory immune activation. In the present study, we constructed a peroxide scavenger mannosylated polymeric albumin manganese dioxide (mSPAM) nanoassembly to catalyze the decomposition of HO responsible for the hyper-activation of pro-inflammatory immune cells. In a detailed manner, we investigated the role of mSPAM nanoassembly in modulating the expression and secretion of pro-inflammatory markers elevated in bacterial lipopolysaccharide (LPS)-mediated endotoxemia during sepsis. Through a facile one-step solution-phase approach, hydrophilic bovine serum albumin reduced manganese dioxide (BM) nanoparticles were synthesized and subsequently self-assembled with cationic mannosylated disulfide cross-linked polyethylenimine (mSP) to formulate mSPAM nanoassembly. In particular, we observed that the highly stable mSPAM nanoassembly suppressed HIF1α expression by scavenging HO in LPS-induced macrophage cells. Initial investigation revealed that a significant reduction of free radicals by the treatment of mSPAM nanoassembly has reduced the infiltration of neutrophils and other leukocytes in a local endotoxemia animal model. Furthermore, therapeutic studies in a systemic endotoxemia model demonstrated that mSPAM treatment reduced TNF-α and IL-6 inflammatory cytokines in serum, in turn circumventing organ damage done by the inflammatory macrophages. Interestingly, we also observed that the reduction of these inflammatory cytokines by mSPAM nanoassembly further prevented IBA-1 immuno-positive microglial cell activation in the brain and consequently improved the cognitive function of the animals. Altogether, the administration of mSPAM nanoassembly scavenged HO and suppressed HIF1α expression in LPS-stimulated macrophages and thereby inhibited the progression of local and systemic inflammation as well as neuroinflammation in an LPS-induced endotoxemia model. This mSPAM nanoassembly system could serve as a potent anti-inflammatory agent, and we further anticipate its successful application in treating various inflammation-related diseases.
Nanoparticle-induced neutrophil apoptosis increases survival in sepsis and alleviates neurological damage in stroke.
Zhang Can Yang,Dong Xinyue,Gao Jin,Lin Wenjing,Liu Ze,Wang Zhenjia
Human neutrophils are the most abundant circulating leukocytes and contribute to acute and chronic inflammatory disorders. Neutrophil apoptosis is programed cell death to maintain immune homeostasis, but inflammatory responses to infections or tissue injury disrupt neutrophil death program, leading to many diseases. Precise control of neutrophil apoptosis may resolve inflammation to return immune homeostasis. Here, we report a method in which doxorubicin (DOX)-conjugated protein nanoparticles (NPs) can in situ selectively target inflammatory neutrophils for intracellular delivery of DOX that induces neutrophil apoptosis. We showed that neutrophil uptake of NPs required their activation and was highly selective. DOX release was triggered by acidic environments in neutrophils, subsequently inhibiting neutrophil transmigration and inflammatory responses. In two disease models, DOX-conjugated NPs notably increased mouse survival in sepsis and prevented brain damage in cerebral ischemia/reperfusion, but the NPs did not suppress systemic immunity. Our studies offer a promising strategy to treat inflammatory diseases.