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Individuals with clonal hematopoiesis of indeterminate potential (CHIP) are at increased risk of aging related health conditions and all-cause mortality, but whether CHIP affects risk of infection is much less clear. Using UK Biobank data, we revealed a positive association between CHIP and incident pneumonia in 438,421 individuals. We show that inflammation enhanced pneumonia risk, as CHIP carriers with a hypomorphic IL6 receptor polymorphism were protected. To better characterize the pathways of susceptibility, we challenged hematopoietic Tet Methylcytosine Dioxygenase 2-knockout ([Tet2.sup.-/-]) and floxed control mice ([Tet2.sup.fl/fl]) with Streptococcus pneumoniae. As with human CHIP carriers, [Tet2.sup.-/-] mice had hematopoietic abnormalities resulting in the expansion of inflammatory monocytes and neutrophils in peripheral blood. Yet, these cells were insufficient in defending against S. pneumoniae and resulted in increased pathology, impaired bacterial clearance, and higher mortality in [Tet2.sup.-/-] mice. We delineated the transcriptional landscape of [Tet2.sup.-/-] neutrophils and found that, while inflammation-related pathways were upregulated in [Tet2.sup.-/-] neutrophils, migration and motility pathways were compromised. Using live-imaging techniques, we demonstrated impairments in motility, pathogen uptake, and neutrophil extracellular trap (NET) formation by [Tet2.sup.-/-] neutrophils. Collectively, we show that CHIP is a risk factor for bacterial pneumonia related to innate immune impairments., Introduction Human aging is accompanied by dysregulation of hematopoiesis in the bone marrow (BM), which may have adverse clinical consequences (1). Hematopoiesis is a tightly regulated process by which hematopoietic [...]

To the Editor: Alcohol-associated liver disease (ALD), one of the major chronic liver diseases worldwide, includes a spectrum of liver disorders from simple steatosis to steatohepatitis and cirrhosis. Patients with [...]

Background Children who experience more than one urinary tract infection (UTI) are at increased risk of kidney scarring due to their UTIs. Girls are at especially high risk for developing kidney scarring as a result of recurrent UTIs. Prior work suggested that neutrophil gelatinase-associated lipocalin (NGAL) may be lower in children with recurrent UTI compared with those without. The objective of this work was to compare urine NGAL concentrations in matched urine samples in girls with single and recurrent UTIs. Methods Girls less than 6 years of age who presented with signs and symptoms of a UTI were eligible for enrollment. Both acute, obtained from residual urine collected as part of their clinical evaluation, and follow-up urine samples, obtained after the completion of antibiotics when the patient was in their usual state of health, were collected from patients. Acute and follow-up urine NGAL concentrations were compared between girls with single and recurrent UTIs, as well as those with negative cultures who served as controls. Results Seventy girls were included in this study, 6 controls, 43 single UTIs, and 20 girls with recurrent UTIs. Patients in the control group had lower median acute NGAL concentrations than either those with single or recurrent UTI. There were no differences in either acute or follow-up urine NGAL concentrations between those with single and recurrent UTIs. Conclusion In this cohort of girls less than 6 years of age, there is no difference in urine NGAL concentrations between those with single and recurrent UTIs., Author(s): Catherine S. Forster [sup.1] [sup.2] , Allison M. Loechtenfeldt [sup.1] , Samir S. Shah [sup.1] , Stuart Goldstein [sup.1] Author Affiliations: (1) grid.239573.9, 0000 0000 9025 8099, Department of [...]

Mice homozygous for the Tyr208Asn amino acid substitution in the carboxy terminus of Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1) (referred to as [Ptpn6.sup.spin] mice) spontaneously develop a severe inflammatory disease resembling neutrophilic dermatosis in humans. Disease in [Ptpn6.sup.spin] mice is characterized by persistent footpad swelling and suppurative inflammation. Recently, in addition to IL-1[alpha] and IL-1R signaling, we demonstrated a pivotal role for several kinases such as SYK, RIPK1, and TAK1 in promoting inflammatory disease in [Ptpn6.sup.spin] mice. In order to identify new kinases involved in SHP-1-mediated inflammation, we took a genetic approach and discovered apoptosis signal-regulating kinases 1 and 2 (ASK1 and ASK2) as novel kinases regulating Ptpn6-mediated footpad inflammation. Double deletion of ASK1 and ASK2 abrogated cutaneous inflammatory disease in [Ptpn6.sup.spin] mice. This double deletion further rescued the splenomegaly and lymphomegaly caused by excessive neutrophil infiltration in [Ptpn6.sup.spin] mice. Mechanistically, ASK regulates [Ptpn6.sup.spin]-mediated disease by controlling proinflammatory signaling in the neutrophils. Collectively, the present study identifies SHP-1 and ASK signaling crosstalk as a critical regulator of IL-1[alpha]-driven inflammation and opens future avenues for finding novel drug targets to treat neutrophilic dermatosis in humans., Introduction Mutations in the PTPN6 gene that encodes for the protein tyrosine phosphatase Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1) have been linked with autoinflammatory and autoimmune diseases [...]

Sites of acute inflammation become austere environments for the procurement of energy. The combination of oxygen depletion (hypoxia) and decreased glucose availability requires surprising metabolic adaptability. In this issue of the JCI, Watts et al. examined the metabolic adaptability of murine neutrophils to the setting of acute pulmonary inflammation elicited by exposure to nebulized endotoxin. While neutrophils are generally considered a primarily glycolytic cell type, Watts et al. used a combination of labeled amino acids and high-resolution proteomics to reveal that the harsh environment of the inflammatory lesion drives neutrophils toward de novo protein synthesis and extracellular protein scavenging as a primary fuel. This study provides compelling evidence that tissue neutrophils scavenge extracellular proteins to fuel carbon metabolism, which aids in de novo protein synthesis and the promotion of an inflammatory phenotype. These observations reveal the surprisingly creative extent to which cells and tissues might adapt to energy-deficient inflammatory environments., Neutrophils are energetically active The acute inflammatory response is characterized by the rapid influx of large numbers of neutrophils into the tissue. Traditionally, it was believed that neutrophils only had [...]

Limiting dysfunctional neutrophilic inflammation while preserving effective immunity requires a better understanding of the processes that dictate neutrophil function in the tissues. Quantitative mass-spectrometry identified how inflammatory murine neutrophils regulated expression of cell surface receptors, signal transduction networks, and metabolic machinery to shape neutrophil phenotypes in response to hypoxia. Through the tracing of labeled amino acids into metabolic enzymes, proinflammatory mediators, and granule proteins, we demonstrated that ongoing protein synthesis shapes the neutrophil proteome. To maintain energy supplies in the tissues, neutrophils consumed extracellular proteins to fuel central carbon metabolism. The physiological stresses of hypoxia and hypoglycemia, characteristic of inflamed tissues, promoted this extracellular protein scavenging with activation of the lysosomal compartment, further driving exploitation of the protein-rich inflammatory milieu. This study provides a comprehensive map of neutrophil proteomes, analysis of which has led to the identification of active catabolic and anabolic pathways that enable neutrophils to sustain synthetic and effector functions in the tissues., Introduction The rapid recruitment of innate immune cells is critical for containing and eradicating infection and the restoration of normal tissue homeostasis. To enable effective immune responses in the tissues, [...]

The tumor microenvironment profoundly influences the behavior of recruited leukocytes and tissue-resident immune cells. These immune cells, which inherently have environmentally driven plasticity necessary for their roles in tissue homeostasis, dynamically interact with tumor cells and the tumor stroma and play critical roles in determining the course of disease. Among these immune cells, neutrophils were once considered much more static within the tumor microenvironment; however, some of these earlier assumptions were the product of the notorious difficulty in manipulating neutrophils in vitro. Technological advances that allow us to study neutrophils in context are now revealing the true roles of neutrophils in the tumor microenvironment. Here we discuss recent data generated by some of these tools and how these data might be synthesized into more elegant ways of targeting these powerful and abundant effector immune cells in the clinic., Introduction Recent years have seen a resurgence in neutrophil biology in the context of cancer. Emerging data show that neutrophils are far from the simple homogeneous population they were once [...]

Upon activation, neutrophils release DNA fibers decorated with antimicrobial proteins, forming neutrophil extracellular traps (NETs) (1-3). Although NETs are bactericidal and contribute to innate host defense, excessive NET formation has been linked to the pathogenesis of autoinflammatory diseases (4,5). However, the mechanisms regulating NET formation, particularly during chronic inflammation, are poorly understood. Here we show that the G protein-coupled receptor (GPCR) CXCR2 mediates NET formation. Downstream analyses showed that CXCR2-mediated NET formation was independent of NADPH oxidase and involved Src family kinases. We show the pathophysiological relevance of this mechanism in cystic fibrosis lung disease, characterized by chronic neutrophilic inflammation (6,7). We found abundant NETs in airway fluids of individuals with cystic fibrosis and mouse cystic fibrosis lung disease, and NET amounts correlated with impaired obstructive lung function. Pulmonary blockade of CXCR2 by intra-airway delivery of small-molecule antagonists inhibited NET formation and improved lung function in vivo without affecting neutrophil recruitment, proteolytic activity or antibacterial host defense. These studies establish CXCR2 as a receptor mediating NADPH oxidase-independent NET formation and provide evidence that this GPCR pathway is operative and druggable in cystic fibrosis lung disease., Neutrophils act as first line of host defense against bacteria and fungi (8). The concept that neutrophils kill pathogens exclusively intracellularly by phagocytosis has been challenged by the finding that [...]

Under normal conditions, there is a paucity of neutrophils within the intestinal mucosa; however, these innate immune cells rapidly infiltrate the mucosa in response to infection and are critical for pathogen control. Unfortunately, these cells can cause extensive damage to the intestine if the initial inflammatory influx is not resolved. Factors that promote resolution of inflammation are of great interest, as they have therapeutic potential for limiting uncontrolled inflammatory damage. In this issue of the JCI, Szabady et al. demonstrate that the multidrug resistance transporter P-glycoprotein (P-gp) secretes endocannabinoids into the intestinal lumen that counteract the proinflammatory actions of the eicosanoid hepoxilin A3, which is secreted into the lumen by the efflux pump MRP2 and serves as a potent neutrophil chemoattractant. Moreover, the antiinflammatory actions of P-gp-secreted endocannabinoids were mediated by peripheral cannabinoid receptor CB2 on neutrophils. Together, the results of this study identify an important mechanism by which endogenous endocannabinoids facilitate the resolution of inflammation; this mechanism has potential to be therapeutically exploited., The search for inflammation-suppressing biolipids A striking histological characteristic of a healthy gut mucosa is the general absence ofneutrophils; however, these acute inflammatory cells are capable of rapid influx into [...]

Regulation of Proteolysis at the Neutrophil-Substrate Interface by Secretory Leukoprotease Inhibitor HUMAN PLASMA AND ITS FILTRATES contain a complex mix of proteinase inhibitors that normally protect connective tissues from uncontrolled [...]

1. Introduction Neutrophilic polymorphonuclear leukocytes (PMNs) are phagocytic cells that constitute the first cellular component of innate immune defense [1]. Quickly reacting to infection and injury, PMNs migrate to sites [...], Accumulation of neutrophils in the site of inflammation is a typical mechanism of innate immunity. The accumulated neutrophils are exposed to stressogenic factors usually associated with inflammation. Here, we studied response of human peripheral blood neutrophils subjected to short, febrile-range heat stress. We show that 90 min heat stress slowed down the spontaneous apoptosis of neutrophils. In the absence of typical markers of apoptosis the heat-shocked neutrophils induced antiinflammatory effect in human monocyte-derived macrophages (hMDMs), yet without being engulfed. Importantly, the expression of FcγRIII (CD16) was sharply reduced. Surprisingly, concentration of the soluble CD16 did not change in heat-shocked neutrophil supernates indicating that the reduction of the cell surface CD16 was achieved mainly by inhibition of fresh CD16 delivery. Inhibitors of 90kDa heat shock protein (HSP90), a molecular chaperone found in membrane platforms together with CD16 and CD11b, significantly increased the observed effects caused by heat shock. The presented data suggest a novel systemic aspect of increased temperature which relies on immediate modification by heat of a neutrophil molecular pattern. This effect precedes cell death and may be beneficial in the initial phase of inflammation providing a nonphlogistic signal to macrophages before it comes from apoptotic cells.