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Introduction In sepsis, an excessive inflammatory response to infection leads to end organ damage (1). After surviving the early, inflammatory phase of sepsis, previously healthy patients can develop post-sepsis immunosuppression [...], As treatment of the early, inflammatory phase of sepsis improves, post-sepsis immunosuppression and secondary infection have increased in importance. How early inflammation drives immunosuppression remains unclear. Although IFN-[gamma] typically helps microbial clearance, we found that increased plasma IFN-[gamma] in early clinical sepsis was associated with the later development of secondary Candida infection. Consistent with this observation, we found that exogenous IFN-[gamma] suppressed macrophage phagocytosis of zymosan in vivo, and antibody blockade of IFN-[gamma] after endotoxemia improved survival of secondary candidemia. Transcriptomic analysis of innate lymphocytes during endotoxemia suggested that NKT cells drove IFN-[gamma] production by NK cells via mTORC1. Activation of invariant NKT (iNKT) cells with glycolipid antigen drove immunosuppression. Deletion of iNKT cells in [Cd1d.sup.-/-] mice or inhibition of mTOR by rapamycin reduced immunosuppression and susceptibility to secondary Candida infection. Thus, although rapamycin is typically an immunosuppressive medication, in the context of sepsis, rapamycin has the opposite effect. These results implicated an NKT cell/mTOR/IFN-[gamma] axis in immunosuppression following endotoxemia or sepsis. In summary, in vivo iNKT cells activated mTORC1 in NK cells to produce IFN-[gamma], which worsened macrophage phagocytosis, clearance of secondary Candida infection, and mortality.

Introduction Type 2 immunity (T2I) mediates host defense against helminthic parasites (1) and facilitates epithelial barrier repair (2). If dysregulated or directed against innocuous antigens (allergens), T2I can also promote [...], Antagonists of the type 1 cysteinyl leukotriene receptor ([CysLT.sub.1]R) are widely used to treat asthma and allergic rhinitis, with variable response rates. Alveolar macrophages express UDP-specific [P2Y.sub.6] receptors that can be blocked by off- target effects of [CysLT.sub.1]R antagonists. Sensitizing intranasal doses of an extract from the house dust mite Dermatophagoides farinae (Df) sharply increased the levels of UDP detected in bronchoalveolar lavage fluid of mice. Conditional deletion of [P2Y.sub.6] receptors before sensitization exacerbated eosinophilic lung inflammation and type 2 cytokine production in response to subsequent Df challenge. [P2Y.sub.6] receptor signaling was necessary for dectin-2-dependent production of protective IL-12p40 and Th1 chemokines by alveolar macrophages, leading to activation of NK cells to generate IFN-[gamma]. Administration of [CysLT.sub.1]R antagonists during sensitization blocked UDP-elicited potentiation of IL-12p40 production by macrophages in vitro, suppressed the Df-induced production of IL-12p40 and IFN-[gamma] in vivo, and suppressed type 2 inflammation only in [P2Y.sub.6]-deficient mice. Thus, [P2Y.sub.6] receptor signaling drives an innate macrophage/IL-12/NK cell/IFN-[gamma] axis that prevents inappropriate allergic type 2 immune responses on respiratory allergen exposure and counteracts the Th2 priming effect of [CysLT.sub.1]R signaling at sensitization. Targeting [P2Y.sub.6] signaling might prove to be a potential additional treatment strategy for allergy.

Epithelial hyperplasia and metaplasia are common features of inflammatory and neoplastic disease, but the basis for the altered epithelial phenotype is often uncertain. Here we show that long-term ciliated cell hyperplasia coincides with mucous (goblet) cell metaplasia after respiratory viral clearance in mouse airways. This chronic switch in epithelial behavior exhibits genetic susceptibility and depends on persistent activation of EGFR signaling to PI3K that prevents apoptosis of ciliated cells and on IL-13 signaling that promotes transdifferentiation of ciliated to goblet cells. Thus, EGFR blockade (using an irreversible EGFR kinase inhibitor designated EKB-569) prevents virus-induced increases in ciliated and goblet cells whereas IL-13 blockade (using s-IL-13R2-Fc) exacerbates ciliated cell hyperplasia but still inhibits goblet cell metaplasia. The distinct effects of EGFR and IL-13 inhibitors after viral reprogramming suggest that these combined therapeutic strategies may also correct epithelial architecture in the setting of airway inflammatory disorders characterized by a similar pattern of chronic EGFR activation, IL-13 expression, and ciliated-to-goblet cell metaplasia. [ABSTRACT FROM AUTHOR]