Neutrophils are the most abundant, short lived, and terminally differentiated leukocytes with distinct tiers of arsenals to counter pathogens. Neutrophils were traditionally considered transcriptionally inactive cells, but recent researches in the field led to a paradigm shift in neutrophil biology and revealed subpopulation heterogeneity, and functions pivotal to immunity and inflammation. Furthermore, recent unfolding of metabolic plasticity in neutrophils has challenged the long-standing concept of their sole dependence on glycolytic pathway. Metabolic adaptations and distinct regulations have been identified which are critical for neutrophil differentiation and functions. The metabolic reprogramming of neutrophils by inflammatory mediators or during pathologies such as sepsis, diabetes, glucose-6-phosphate dehydrogenase deficiency, glycogen storage diseases (GSDs), systemic lupus erythematosus (SLE), rheumatoid arthritis, and cancer are now being explored. In this review, we discuss recent developments in understanding of the metabolic regulation, that may provide clues for better management and newer therapeutic opportunities for neutrophil centric immuno-deficiencies and inflammatory disorders.

Injury to the central nervous system initiates an uncontrolled inflammatory response that results in both tissue repair and destruction. Here, we showed that, in rodents and humans, injury to the spinal cord triggered surface expression of CD95 ligand (CD95L, FasL) on peripheral blood myeloid cells. CD95L stimulation of CD95 on these cells activated phosphoinositide 3-kinase (PI3K) and metalloproteinase-9 (MMP-9) via recruitment and activation of Syk kinase, ultimately leading to increased migration. Exclusive CD95L deletion in myeloid cells greatly decreased the number of neutrophils and macrophages infiltrating the injured spinal cord or the inflamed peritoneum after thioglycollate injection. Importantly, deletion of myeloid CD95L, but not of CD95 on neural cells, led to functional recovery of spinal injured animals. Our results indicate that CD95L acts on peripheral myeloid cells to induce tissue damage. Thus, neutralization of CD95L should be considered as a means to create a controlled beneficial inflammatory response.

Adult neurogenesis persists in the subventricular zone and the dentate gyrus and can be induced upon central nervous system injury. However, the final contribution of newborn neurons to neuronal networks is limited. Here we show that in neural stem cells, stimulation of the "death receptor" CD95 does not trigger apoptosis but unexpectedly leads to increased stem cell survival and neuronal specification. These effects are mediated via activation of the Src/PI3K/AKT/mTOR signaling pathway, ultimately leading to a global increase in protein translation. Induction of neurogenesis by CD95 was further confirmed in the ischemic CA1 region, in the naive dentate gyrus, and after forced expression of CD95L in the adult subventricular zone. Lack of hippocampal CD95 resulted in a reduction in neurogenesis and working memory deficits. Following global ischemia, CD95-mediated brain repair rescued behavioral impairment. Thus, we identify the CD95/CD95L system as an instructive signal for ongoing and injury-induced neurogenesis.

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Chemotaxis promotes neutrophil participation in cellular defense by enabling neutrophil migration to infected tissue and is controlled by persistent cell polarization. One long-standing question of neutrophil polarity has been how the pseudopod and the uropod are coordinated. In our previous report, we suggested that Rho GTPase Cdc42 controls neutrophil polarity through CD11b signaling at the uropod, albeit through an unknown mechanism. Here, we show that Cdc42 controls polarity, unexpectedly, via its effector WASp. Cdc42 controls WASp activation and its distant localization to the uropod. At the uropod, WASp regulates the reorganization of CD11b integrin into detergent resistant membrane domains; in turn, CD11b recruits the microtubule end binding protein EB1 to capture and stabilize microtubules at the uropod. This organization is necessary to maintain neutrophil polarity during migration and is critical for neutrophil emigration into inflamed lungs. These results suggest unrecognized mechanism of neutrophil polarity in which WASp mediates long-distance control of the uropod by Cdc42 to maintain a proper balance between the pseudopod and the uropod. IntroductionNeutrophils are the most abundant leukocyte and fastest moving cell in the body. Neutrophils play a central role in innate immunity as cellular defense against infecting microorganisms and inflammatory processes and can contribute to hyperinflammatory reactions causing tissue injury. Neutrophils move rapidly toward sites of infection through a multiple-step process that involves tethering, rolling, adhesion, and transmigration to reach the site of infection in the tissue. Moreover, a new step in the neutrophil extravasation cascade, so-called locomotion, has been recently identified where neutrophils crawl onto endothelium toward the nearest endothelial junctions before transmigrating into tissues. [1][2][3] Failure to regulate any of these events of neutrophil extravasation may lead to abnormal innate immune responses, including immunodeficiency or aberrant inflammatory reactions. Therefore, understanding the molecular mechanisms that control neutrophil migration is of significant therapeutic importance.Neutrophils are one of the fastest migrating cells in response to a shallow chemoattractant gradient. Migrating neutrophils are highly polarized cells, which enables them to persistently migrate along the chemotactic gradient. During this process, filamentous actin (F-actin) polymerizes asymmetrically at the cell leading edge, and provides the protrusive forces to propel the cell membrane forward. At the same time, lateral membrane protrusions (so-called secondary/abnormal protrusions) are inhibited by actomyosin contractile complexes forming along the cell sides and the trailing edge, or uropod. [4][5][6] Members of the Rho GTPase family, including Rho, Rac, and Cdc42, are key regulators of chemotaxis. They cycle between an inactive, GDP-bound and active, GTP-bound forms via guanine nucleotide exchange factors (GEFs) and GTPaseactivating proteins (GAP...

Hematopoietic stem cell (HSC) transplantation can restore a new functional hematopoietic system in recipients in cases where the recipient’s own system is not functional, or for example, leukemic. However, the number of available donor HSCs is sometimes too low for successful transplantation. Expansion of HSCs and thus, HSC self-renewal ex vivo would greatly improve transplantation therapy in the clinic. In vivo, HSCs expand significantly in the niche, but establishing protocols that result in HSC expansion ex vivo remains challenging. In this review, we discuss current knowledge of niche biology, the intrinsic regulators of HSC self-renewal in vivo, and introduce novel niche-informed strategies of HSC expansion ex vivo.

Neutrophils expel extracellular traps (NETs) to entrap and exterminate the invaded micro-organisms. Acute/chronic inflammatory disorders are often observed with aberrantly enhanced NETs formation and high nitric oxide (NO) availability. Recent study from this laboratory demonstrated release of NETs from human neutrophils following treatment with SNP or SNAP. This study is an extension of our previous finding to explore the extracellular bacterial killing, source of DNA in the expelled NETs, their ability to induce proinflammatory cytokines release from platelets/THP-1 cells, and assessment of NO-mediated free radical formation by using a consistent NO donor, DETA-NONOate. NO-mediated NETs exhibited extracellular bacterial killing as determined by colony forming units. NO-mediated NETs formation was due to the activation of NADPH oxidase and myeloperoxidase. NO-or PMA-mediated NETs were positive for both nuclear and mitochondrial DNA as well as proteolytic enzymes. Incubation of NETs with human platelets enhanced the release of IL-1b and IL-8, while with THP-1 cells, release of IL-1b, IL-8, and TNFa was observed. This study demonstrates that NO by augmenting enzymatic free radical generation release NETs to promote extracellular bacterial killing. These NETs were made up of mitochondrial and nuclear DNA and potentiated release of proinflammatory cytokines. ' 2011 International Society for Advancement of Cytometry Key terms nitric oxide; neutrophil extracellular traps; NADPH-oxidase; myeloperoxidase; inflammatory cytokine; mitochondrial and nuclear DNA

Key Points ATF3 inhibits lipopolysaccharide-driven CXCL1 production by airway epithelia. ATF3 controls neutrophil recruitment to the wild-type lung and chemotaxis in vitro via TIAM2 expression.