Long-Term Microgliosis Driven by Acute Systemic Inflammation.

Severe sepsis, a systemic inflammatory response to infection, is an increasing cause of morbidity in intensive care units. During sepsis, the vasculature is profoundly altered, leading to release of microbial virulence factors and proinflammatory mediators to surrounding tissue, causing severe systemic inflammatory responses and hypoxic injury of multiple organs. To date, multiple studies have explored pathologic conditions in many vital organs, including lungs, liver, and kidneys. Although data suggest that sepsis is emerging as a key driver of chronic brain dysfunction, the immunological consequence of severe inflammatory responses in the brain remain poorly understood. In this study, we used C57BL/6 sepsis mouse models to establish a disease phenotype in which septic mice with various degrees of severity recover. In the early phases of sepsis, monocytes infiltrate the brain with significantly elevated proinflammatory cytokine levels. In recovered animals, monocytes return to vehicle levels, but the number of brain-resident microglia is significantly increased in the cortex, the majority of which remain activated. The increase in microglia number is mainly due to self-proliferation, which is completely abolished in CCR2 knockout mice. Collectively our data suggest that early monocyte infiltration causes permanent changes to microglia during sepsis, which may ultimately dictate the outcome of future infections and neuropathological diseases.

Neutrophil heterogeneity in complement C1q expression associated with sepsis mortality.

Sepsis is a life-threatening systemic inflammatory condition causing approximately 11 million annual deaths worldwide. Although key hyperinflammation-based organ dysfunctions that drive disease pathology have been recognized, our understanding of the factors that predispose patients to septic mortality is limited. Due to the lack of reliable prognostic measures, the development of appropriate clinical management that improves patient survival remains challenging. Here, we discovered that a subpopulation of CD49chigh neutrophils with dramatic upregulation of the complement component 1q (C1q) gene expression arises during severe sepsis. We further found that deceased septic patients failed to maintain C1q protein expression in their neutrophils, whereas septic survivors expressed higher levels of C1q. In mouse sepsis models, blocking C1q with neutralizing antibodies or conditionally knocking out C1q in neutrophils led to a significant increase in septic mortality. Apoptotic neutrophils release C1q to control their own clearance in critically injured organs during sepsis; thus, treatment of septic mice with C1q drastically increased survival. These results suggest that neutrophil C1q is a reliable prognostic biomarker of septic mortality and a potential novel therapeutic target for the treatment of sepsis.

Co-Encapsulation and Co-Delivery of Peptide Drugs via Polymeric Nanoparticles.

Combination therapy is a promising form of treatment. In particular, co-treatment of P3 and QBP1 has been shown to enhance therapeutic effect in vivo in treating polyglutamine diseases. These peptide drugs, however, face challenges in clinical administration due to poor stability, inability to reach intracellular targets, and lack of method to co-deliver both drugs. Here we demonstrate two methods of co-encapsulating the peptide drugs via polymer poly(ethylene glycol)-block-polycaprolactone (PEG-b-PCL) based nanoparticles. Nanoparticles made by double emulsion were 100⁻200 nm in diameter, with drug encapsulation efficiency of around 30%. Nanoparticles made by nanoprecipitation with lipid 1-palmitoyl-2-oleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (POPG) were around 250⁻300 nm in diameter, with encapsulation efficiency of 85⁻100%. Particles made with both formulations showed cellular uptake when decorated with a mixture of peptide ligands that facilitate endocytosis. In vitro assay showed that nanoparticles could deliver bioactive peptides and encapsulation by double emulsion were found to be more effective in rescuing cells from polyglutamine-induced toxicity.