25 research outputs found
Functions preserving nonnegativity of matrices
The main goal of this work is to determine which entire functions preserve
nonnegativity of matrices of a fixed order -- i.e., to characterize entire
functions with the property that is entrywise nonnegative for every
entrywise nonnegative matrix of size . Towards this goal, we
present a complete characterization of functions preserving nonnegativity of
(block) upper-triangular matrices and those preserving nonnegativity of
circulant matrices. We also derive necessary conditions and sufficient
conditions for entire functions that preserve nonnegativity of symmetric
matrices. We also show that some of these latter conditions characterize the
even or odd functions that preserve nonnegativity of symmetric matrices.Comment: 20 pages; expanded and corrected to reflect referees' remarks; to
appear in SIAM J. Matrix Anal. App
Increased Adhesive Potential of Antiphospholipid Syndrome Neutrophils Mediated by ĂÂČ2 Integrin MacĂą 1
Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153125/1/art41057.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153125/2/art41057_am.pd
Heterotypic intercellular interactions as regulators of NETosis
Neutrophil extracellular traps (NETs) are chromatin-derived webs extruded from neutrophils in response to either infection or sterile stimulation with chemicals, cytokines, or microbial products. The vast majority of studies have characterized NET release (also called NETosis) in pure neutrophil cultures in vitro. The situation is surely more complex in vivo as neutrophils constantly sample not only pathogens and soluble mediators, but also signals from cellular partners including platelets and endothelial cells. This complexity is beginning to be explored by studies utilizing in vitro co-culture, as well as animal models of sepsis, infective endocarditis, lung injury, and thrombosis. Indeed, various selectins, integrins, and surface glycoproteins have been implicated in platelet-neutrophil interactions that promote NETosis, albeit with disparate results across studies. NETosis can also clearly be regulated by soluble mediators derived from platelets such as eicosanoids, chemokines, and alarmins. Beyond platelets, the role of the endothelium in modulating NETosis is being increasingly revealed, with adhesive interactions likely priming neutrophils toward NETosis. The fact that the same selectins and surface glycoproteins may be expressed by both platelets and endothelial cells complicates the interpretation of in vivo data. In summary, we suggest in this review that the engagement of neutrophils with activated cellular partners provides an important in vivo signal or hit toward NETosis. Studies should therefore increasingly consider the triumvirate of neutrophils, platelets, and the endothelium when exploring NETosis, especially in disease states
NOD2 signaling contributes to the innate immune response against helper-dependent adenovirus vectors independently of MyD88 in vivo
We previously demonstrated that Toll-like receptor/myeloid differentiation primary response gene 88 (MyD88) signaling is required for maximal innate and acquired [T helper cell type 1 (Th1)] immune responses following systemic administration of helper-dependent adenoviral vectors (HDAds). However, MyD88-deficient mice injected with HDAdLacZ exhibited only partial reduction of innate immune cytokine expression compared with wild-type mice, suggesting MyD88-independent pathways also respond to HDAds. We now show that NOD2, a nucleotide-binding and oligomerization domain (NOD)-like receptor known to detect muramyl dipeptides in bacterial peptidoglycans, also contributes to innate responses to HDAds, but not to humoral or Th1 immune responses. We established NOD2/MyD88 double-deficient mice that, when challenged with HDAds, showed a significant reduction of the innate response compared with mice deficient for either gene singly, suggesting that NOD2 signaling contributes to the innate response independently of MyD88 signaling following systemic administration of HDAds. In addition, NOD2-deficient mice exhibited significantly higher transgene expression than did wild-type mice at an early time point (before development of an acquired response), but not at a later time point (after development of an acquired response). These results indicate that the intracellular sensor NOD2 is required for innate responses to HDAds and can limit transgene expression during early phases of infection
The IRE1α Stress Signaling Axis Is a Key Regulator of Neutrophil Antimicrobial Effector Function
Activation of the endoplasmic reticulum stress sensor, IRE1α, is required for effective immune responses against bacterial infection and is associated with human inflammatory diseases where neutrophils are a key immune component. However, the specific role of IRE1α in regulating neutrophil effector function has not been studied. Here we show that infection-induced IRE1α activation licenses neutrophil antimicrobial capacity, including IL-1ÎČ production, formation of neutrophil extracellular traps (NETs), and MRSA killing. Inhibition of IRE1α diminished production of mitochondrial reactive oxygen species (mROS) and decreased CASPASE-2 activation, which both contributed to neutrophil antimicrobial activity. Mice deficient in CASPASE-2 or neutrophil IRE1α were highly susceptible to MRSA infection and failed to effectively form NETs in the subcutaneous abscess. IRE1α activation enhanced calcium influx and citrullination of histone H3 independently of mROS production, suggesting that IRE1α coordinates multiple pathways required for NET formation. Our data demonstrate that the IRE1α-CASPASE-2 axis is a major driver of neutrophil activity against MRSA infection and highlight the importance of IRE1α in neutrophil antibacterial function
NOD2 Signaling Contributes to the Innate Immune Response Against Helper-Dependent Adenovirus Vectors Independently of MyD88 In Vivo
Cytokine-Conditioned Dendritic Cells Induce Humoral Tolerance to Protein Therapy in Mice
Ectonucleotidase-Mediated Suppression of Lupus Autoimmunity and Vascular Dysfunction
ObjectivesCD39 and CD73 are surface enzymes that jut into the extracellular space where they mediate the step-wise phosphohydrolysis of the autocrine and paracrine danger signals ATP and ADP into anti-inflammatory adenosine. Given the role of vascular and immune cellsâ âpurinergic haloâ in maintaining homeostasis, we hypothesized that the ectonucleotidases CD39 and CD73 might play a protective role in lupus.MethodsLupus was modeled by intraperitoneal administration of pristane to three groups of mice: wild-type (WT), CD39â/â, and CD73â/â. After 36âweeks, autoantibodies, endothelial function, kidney disease, splenocyte activation/polarization, and neutrophil activation were characterized.ResultsAs compared with WT mice, CD39â/â mice developed exaggerated splenomegaly in response to pristane, while both groups of ectonucleotidase-deficient mice demonstrated heightened anti-ribonucleoprotein production. The administration of pristane to WT mice triggered only subtle dysfunction of the arterial endothelium; however, both CD39â/â and CD73â/â mice demonstrated striking endothelial dysfunction following induction of lupus, which could be reversed by superoxide dismutase. Activated B cells and plasma cells were expanded in CD73â/â mice, while deficiency of either ectonucleotidase led to expansion of TH17 cells. CD39â/â and CD73â/â mice demonstrated exaggerated neutrophil extracellular trap release, while CD73â/â mice additionally had higher levels of plasma cell-free DNA.ConclusionThese data are the first to link ectonucleotidases with lupus autoimmunity and vascular disease. New therapeutic strategies may harness purinergic nucleotide dissipation or signaling to limit the damage inflicted upon organs and blood vessels by lupus
Endoplasmic reticulum stress sensor IRE1α propels neutrophil hyperactivity in lupus
Neutrophils amplify inflammation in lupus through the release of neutrophil extracellular traps (NETs). The endoplasmic reticulum stress sensor inositol-requiring enzyme 1 α (IRE1α) has been implicated as a perpetuator of inflammation in various chronic diseases; however, IRE1α has been little studied in relation to neutrophil function or lupus pathogenesis. Here, we found that neutrophils activated by lupus-derived immune complexes demonstrated markedly increased IRE1α ribonuclease activity. Importantly, in neutrophils isolated from patients with lupus, we also detected heightened IRE1α activity that was correlated with global disease activity. Immune complexâstimulated neutrophils produced both mitochondrial ROS (mitoROS) and the activated form of caspase-2 in an IRE1α-dependent fashion, whereas inhibition of IRE1α mitigated immune complexâmediated NETosis (in both human neutrophils and a mouse model of lupus). Administration of an IRE1α inhibitor to lupus-prone MRL/lpr mice over 8 weeks reduced mitoROS levels in peripheral blood neutrophils, while also restraining plasma cell expansion and autoantibody formation. In summary, these data identify a role for IRE1α in the hyperactivity of lupus neutrophils and show that this pathway is upstream of mitochondrial dysfunction, mitoROS formation, and NETosis. We believe that inhibition of the IRE1α pathway is a novel strategy for neutralizing NETosis in lupus, and potentially other inflammatory conditions
Whole-exome sequencing identifies mutations in the nucleoside transporter gene SLC29A3 in dysosteosclerosis, a form of osteopetrosis
Dysosteosclerosis (DSS) is the form of osteopetrosis distinguished by the presence of skin findings such as red-violet macular atrophy, platyspondyly and metaphyseal osteosclerosis with relative radiolucency of widened diaphyses. At the histopathological level, there is a paucity of osteoclasts when the disease presents. In two patients with DSS, we identified homozygous or compound heterozygous missense mutations in SLC29A3 by whole-exome sequencing. This gene encodes a nucleoside transporter, mutations in which cause histiocytosisâlymphadenopathy plus syndrome, a group of conditions with little or no skeletal involvement. This transporter is essential for lysosomal function in mice. We demonstrate the expression of Slc29a3 in mouse osteoclasts in vivo. In monocytes from patients with DSS, we observed reduced osteoclast differentiation and function (demineralization of calcium surface). Our report highlights the pleomorphic consequences of dysfunction of this nucleoside transporter, and importantly suggests a new mechanism for the control of osteoclast differentiation and function