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We describe a previously unappreciated role for Bruton's tyrosine kinase (BTK) in fungal immune surveillance against aspergillosis, an unforeseen complication of BTK inhibitors (BTKi) used for treating B cell lymphoid malignancies. We studied BTK-dependent fungal responses in neutrophils from diverse populations, including healthy donors, patients who were treated with BTKi, and X-linked agammaglobulinemia patients. Upon fungal exposure, BTK was activated in human neutrophils in a TLR2-, Dectin-1-, and Fc[gamma]R-dependent manner, triggering the oxidative burst. BTK inhibition selectively impeded neutrophil-mediated damage to Aspergillus hyphae, primary granule release, and the fungus-induced oxidative burst by abrogating NADPH oxidase subunit [p40.sup.phox] and GTPase RAC2 activation. Moreover, neutrophil-specific Btk deletion in mice enhanced aspergillosis susceptibility by impairing neutrophil function, not recruitment or lifespan. Conversely, GM-CSF partially mitigated these deficits by enhancing [p47.sup.phox] activation. Our findings underline the crucial role of BTK signaling in neutrophils for antifungal immunity and provide a rationale for GM-CSF use to offset these deficits in patients who are susceptible., Introduction Invasive aspergillosis (IA), most often caused by the ubiquitous inhaled mold Aspergillus fumigatus, is an opportunistic fungal infection that exploits numeric or functional neutrophil defects (1-3). IA affects over [...]

Autoimmune diseases (ADs) constitute about one hundred and fifty conditions that often afflict people in the prime of their life. ADs are strikingly more common in women and affect around [...]

#MeToo in academia The #MeToo movement has taken on sexual harassment in the workplace and served to inform the world that these unacceptable and illegal acts have become commonplace, including [...]

BACKGROUND. Fasting and [NAD.sup.+]-boosting compounds, including [NAD.sup.+] precursor nicotinamide riboside (NR), confer antiinflammatory effects. However, the underlying mechanisms and therapeutic potential are incompletely defined. METHODS. We explored the underlying biology in myeloid cells from healthy volunteers following in vivo placebo or NR administration and subsequently tested the findings in vitro in monocytes extracted from patients with systemic lupus erythematosus (SLE). RESULTS. RNA-Seq of unstimulated and LPS-activated monocytes implicated NR in the regulation of autophagy and type I IFN signaling. In primary monocytes, NR blunted LPS-induced IFN-[beta] production, and genetic or pharmacological disruption of autophagy phenocopied this effect. Given that [NAD.sup.+] is a coenzyme in oxidoreductive reactions, metabolomics was performed and identified that NR increased the inosine level. Inosine supplementation similarly blunted autophagy and IFN-[beta] release. Finally, because SLE exhibits type I IFN dysregulation, we assessed the NR effect on monocytes from patients with SLE and found that NR reduced autophagy and IFN-[beta] release. CONCLUSION. We conclude that NR, in an [NAD.sup.+]-dependent manner and in part via inosine signaling, mediated suppression of autophagy and attenuated type I IFN in myeloid cells, and we identified NR as a potential adjunct for SLE management. TRIAL REGISTRATION. ClinicalTrials.gov registration numbers NCT02812238, NCT00001846, and NCT00001372. FUNDING. This work was supported by the NHLBI and NIAMS Intramural Research divisions., Introduction Caloric restriction, intermittent fasting, time-restricted feeding, and fasting mimetic diets confer immunomodulatory effects, including amelioration of inflammatory diseases (1-6) and blunting of the NLRP3 inflammasome, circulating cytokines, and acute-phase [...]

The etiopathogenesis of systemic lupus erythematosus (SLE), a clinically heterogeneous multisystemic syndrome that derives its name from the initial characterization of facial lesions that resemble the bite of a wolf, is considered a complex, multifactorial interplay between underlying genetic susceptibility factors and the environment. Prominent pathogenic factors include the induction of aberrant cell death pathways coupled with defective cell death clearance mechanisms that promote excessive externalization of modified cellular and nuclear debris with subsequent loss of tolerance to a wide variety of autoantigens and innate and adaptive immune dysregulation. While abnormalities in adaptive immunity are well recognized and are key to the pathogenesis of SLE, recent findings have emphasized fundamental roles of the innate immune system in the initiation and propagation of autoimmunity and the development of organ damage in this disease. This Review focuses on recent discoveries regarding the role of components of the innate immune system, specifically neutrophils and interferons, in promoting various aspects of lupus pathogenesis, with potential implications for novel therapeutic strategies., Introduction Systemic lupus erythematosus (SLE) is an autoimmune syndrome of unclear etiology that predominantly affects women and disproportionately afflicts minorities (1). Lupus derives its name from the Latin word for [...]

Recent evidence suggests that enhanced neutrophil extracellular trap (NET) formation activates plasmacytoid dendritic cells and serves as a source of autoantigens in SLE. We propose that aberrant NET formation is [...]

BACKGROUNDFasting and NAD+-boosting compounds, including NAD+ precursor nicotinamide riboside (NR), confer antiinflammatory effects. However, the underlying mechanisms and therapeutic potential are incompletely defined.METHODSWe explored the underlying biology in myeloid cells from healthy volunteers following in vivo placebo or NR administration and subsequently tested the findings in vitro in monocytes extracted from patients with systemic lupus erythematosus (SLE).RESULTSRNA-Seq of unstimulated and LPS-activated monocytes implicated NR in the regulation of autophagy and type I IFN signaling. In primary monocytes, NR blunted LPS-induced IFN-β production, and genetic or pharmacological disruption of autophagy phenocopied this effect. Given that NAD+ is a coenzyme in oxidoreductive reactions, metabolomics was performed and identified that NR increased the inosine level. Inosine supplementation similarly blunted autophagy and IFN-β release. Finally, because SLE exhibits type I IFN dysregulation, we assessed the NR effect on monocytes from patients with SLE and found that NR reduced autophagy and IFN-β release.CONCLUSIONWe conclude that NR, in an NAD+-dependent manner and in part via inosine signaling, mediated suppression of autophagy and attenuated type I IFN in myeloid cells, and we identified NR as a potential adjunct for SLE management.TRIAL REGISTRATIONClinicalTrials.gov registration numbers NCT02812238, NCT00001846, and NCT00001372.FUNDINGThis work was supported by the NHLBI and NIAMS Intramural Research divisions. [ABSTRACT FROM AUTHOR]