Neutrophil migration is critical for pathogen clearance and host survival during severe sepsis. Interaction of neutrophil adhesion receptors with ligands on endothelial cells results in firm adhesion of the circulating neutrophils, followed by neutrophil activation and directed migration to sites of infection through the basement membrane and interstitial extracellular matrix. Proteolytic enzymes and reactive oxygen species are produced and released by neutrophils in response to a variety of inflammatory stimuli. Although these mediators are important for host defense, they also promote tissue damage. Excessive neutrophil migration during the early stages of sepsis may lead to an exaggerated inflammatory response with associated tissue damage and subsequent organ dysfunction. On the other hand, dysregulation of migration and insufficient migratory response that occurs during the latter stages of severe sepsis contributes to neutrophils’ inability to contain and control infection and impaired wound healing. This review discusses the major steps and associated molecules involved in the balance of neutrophil trafficking, the precise regulation of which during sepsis spells life or death for the host.

Key Points• Integrin a 3 b 1 (VLA-3; CD49c/CD29) is significantly upregulated on neutrophils from human septic patients and mouse models of sepsis.• a 3 b 1 high granulocytes displayed hyperinflammatory phenotypes and inhibition of a 3 b 1 improved survival in septic mice.Integrin-mediated migration of neutrophils to infected tissue sites is vital for pathogen clearance and therefore host survival. Although b 2 integrins have been shown to mediate neutrophil transendothelial migration during systemic and local inflammation, relatively little information is available regarding neutrophil migration in sepsis beyond the endothelial cell layer. In this study, we report that integrin a 3 b 1 (VLA-3; CD49c/CD29) is dramatically upregulated on neutrophils isolated from both human septic patients and in mouse models of sepsis. Compared with the a 3 b 1 low granulocytes, a 3 b 1 high cells from septic animals displayed hyperinflammatory phenotypes. Administration of a a 3 b 1 blocking peptide and conditional deletion of a 3 in granulocytes significantly reduced the number of extravasating neutrophils and improved survival in septic mice. In addition, expression of a 3 b 1 on neutrophils was associated with Toll-like receptor-induced inflammatory responses and cytokine productions. Thus, our results show that a 3 b 1 is a novel marker of tissue homing and hyperresponsive neutrophil subtypes in sepsis, and blocking of a 3 b 1 may represent a new therapeutic approach in sepsis treatment. (Blood. 2014;124(24):3515-3523)

The NMR solution structure is reported of a duplex, 59GUGAAGCCCGU/39UCACAGGAGGC, containing a 4 @ 4 nucleotide internal loop from an R2 retrotransposon RNA. The loop contains three sheared purine-purine pairs and reveals a structural element found in other RNAs, which we refer to as the 3RRs motif. Optical melting measurements of the thermodynamics of the duplex indicate that the internal loop is 1.6 kcal/mol more stable at 37°C than predicted. The results identify the 3RRs motif as a common structural element that can facilitate prediction of 3D structure. Known examples include internal loops having the pairings: 59GAA/39AGG, 59GAG/39AGG, 59GAA/39AAG, and 59AAG/39AGG. The structural information is compared with predictions made with the MC-Sym program.

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 brainresident 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.

Aberrant activation of neutrophils during sepsis results in the widespread release of pro-inflammatory mediators, leading to multi-organ system failure and death. However, aberrant activation of neutrophils during sepsis results in the widespread release of harmful inflammatory mediators causing host tissue injuries that can lead to multi organ system failure and death. One of the pivotal components of neutrophil migration during inflammation is the expression of surface integrins. In this study, we show that administration of a cyclic analog of RGD peptide (Arg-Gly-Asp) significantly reduced the number of tissue-invading neutrophils and the degree of sepsis-induced lethality in mice as compared to control peptide. Secondly, β1 integrin (CD29) was highly up-regulated on the neutrophils isolated from both septic patients and animals. Finally, conditional genetic ablation of β1 integrin from granulocytes also improved survival and bacterial clearance in septic animals Thus, our results indicate that expression of β1 integrin is important for modulating neutrophil trafficking during sepsis, and that therapeutics designed against β1 integrins may be beneficial.