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The lung naturally resists Aspergillus fumigatus (Af) in healthy individuals, but multiple conditions can disrupt this resistance, leading to lethal invasive infections. Core processes of natural resistance and its breakdown are undefined. We investigated three distinct conditions predisposing to lethal aspergillosis—severe SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, influenza A viral pneumonia, and systemic corticosteroid use—in human patients and murine models. We found a conserved and essential coupling of innate B1a lymphocytes, Af-binding natural immunoglobulin G antibodies, and lung neutrophils. Failure of this axis concealed Af from neutrophils, allowing rapid fungal invasion and disease. Reconstituting the axis with immunoglobulin therapy reestablished resistance, thus representing a realistic pathway to repurpose currently available therapies. Together, we report a vital host resistance pathway that is responsible for protecting against life-threatening aspergillosis in the context of distinct susceptibilities. Avoiding acquired aspergillosis: Avoiding acquired Aspergillosis Healthy humans are able to maintain protection against Aspergillus fumigatus (Af) infection despite frequent exposure to this fungus. However, in a subset of individuals, Af is able to establish infection in the lung. Here, Sarden et al. aimed to characterize the mechanism by which resistance to Af fails in some individuals. The authors found that an axis consisting of innate B1a cells, natural IgG antibodies, and neutrophils is essential for maintaining protection against Af infection in preclinical models. This axis can be disrupted by factors ranging from influenza A and SARS-CoV-2 infection to corticosteroid treatment. Importantly, the authors showed that re-establishing this axis, including by administration of Af¬-reactive antibodies, can protect mice, highlighting a potential treatment. -CM [ABSTRACT FROM AUTHOR]

Neutrophils are recruited from the brood to sites of sterile inflammation, where they contribute to wound healing but may also cause tissue damage. By using spinning disk confocal intravital microscopy, we examined the kinetics and molecular mechanisms of neutrophil recruitment to sites of focal hepatic necrosis in vivo. Adenosine triphosphate released from necrotic cells activated the Nlrp3 inflammasome to generate an inflammatory microenvironment that alerted circulating neutrophils to adhere within liver sinusoids. Subsequently, generation of an intravascular chemokine gradient directed neutrophil migration through healthy tissue toward foci of damage. Lastly, formyl-peptide signals released from necrotic cells guided neutrophils through nonperfused sinusoids into the injury. Thus, dynamic in vivo imaging revealed a multistep hierarchy of directional cues that guide neutrophil localization to sites of sterile inflammation. 10.1126/science.1195491

The article offers information about how dipeptidase-1 has governed renal inflammation during ischemia reperfusion injury. It mentions that mechanisms that drive leukocyte recruitment to the kidney as incompletely understood. Dipeptidase-1 (DPEP1) as a major neutrophil adhesion receptor highly expressed on proximal tubular cells and peritubular capillaries of the kidney.

The article offers information on the mechanism of glucocorticoid-mediated sensitization to ferroptosis bearing clinical and therapeutic implications. It demonstrate that dexamethasone sensitizes to ferroptosis, a form of iron-catalyzed necrosis, previously suggested to contribute to diseases such as acute kidney injury, myocardial infarction, and stroke e triggered by glutathione (GSH) depletion.

Dexamethasone is widely used as an immunosuppressive therapy and recently as COVID-19 treatment. Here, we demonstrate that dexamethasone sensitizes to ferroptosis, a form of iron-catalyzed necrosis, previously suggested to contribute to diseases such as acute kidney injury, myocardial infarction, and stroke, all of which are triggered by glutathione (GSH) depletion. GSH levels were significantly decreased by dexamethasone. Mechanistically, we identified that dexamethasone up-regulated the GSH metabolism regulating protein dipeptidase-1 (DPEP1) in a glucocorticoid receptor (GR)-dependent manner. DPEP1 knockdown reversed the phenotype of dexamethasone-induced ferroptosis sensitization. Ferroptosis inhibitors, the DPEP1 inhibitor cilastatin, or genetic DPEP1 inactivation reversed the dexamethasone-induced increase in tubular necrosis in freshly isolated renal tubules. Our data indicate that dexamethasone sensitizes to ferroptosis by a GR-mediated increase in DPEP1 expression and GSH depletion. Together, we identified a previously unknown mechanism of glucocorticoid-mediated sensitization to ferroptosis bearing clinical and therapeutic implications.