IL-22 Binding Protein Controls IL-22-Driven Bleomycin-Induced Lung Injury.

The high mortality rates of acute lung injury and acute respiratory distress syndrome challenge the field to identify biomarkers and factors that can be exploited for therapeutic approaches. IL-22 is a cytokine that has antibacterial and reparative properties in the lung. However, it also can exacerbate inflammation and requires tight control by the extracellular inhibitory protein known as IL-22 binding protein (IL-22BP) (Il22ra2). This study showed the necessity of IL-22BP in controlling and preventing acute lung injury using IL-22BP knockout mice (Il22ra2-/-) in the bleomycin model of acute lung injury/acute respiratory distress syndrome. Il22ra2-/- mice had greater sensitivity (weight loss and death) and pulmonary inflammation in the acute phase (first 7 days) of the injury compared with wild-type C57Bl/6 controls. The inflammation was driven by excess IL-22 production, inducing the influx of pathogenic IL-17A+ γδ T cells to the lung. Interestingly, this inflammation was initiated in part by the noncanonical IL-22 signaling to macrophages, which express the IL-22 receptor (Il22ra1) in vivo after bleomycin challenge. This study further showed that IL-22 receptor alpha-1+ macrophages can be stimulated by IL-22 to produce a number of IL-17-inducing cytokines such as IL-1ß, IL-6, and transforming growth factor-ß1. Together, the results suggest that IL-22BP prevents IL-22 signaling to macrophages and reduces bleomycin-mediated lung injury.

Hematopoietic 12/15-lipoxygenase activity negatively contributes to fungal-associated allergic asthma.

Asthma is one of the most common noncommunicable diseases in the world. Approximately 30% of severe cases are associated with fungal sensitization, often associated with allergy to the opportunistic mold Aspergillus fumigatus. Leukotrienes, immunopathogenic mediators derived from the metabolism of arachidonic acid (AA) by 5-lipoxygenase (5-LOX), are often elevated in severe asthma. As such, these mediators are Food and Drug Administration-approved therapeutic targets of the antiasthmatic drugs Zileuton/Zyflo and Singulair/Montelukast. A second enzyme involved in AA metabolism is 12/15-lipoxygenase (12/15-LOX; Alox15). Here, C57BL/6 wild-type (WT) mice subjected to experimental fungal asthma had increased expression of Alox15 mRNA and increased levels of 12-HETE, a product of 12/15-LOX activity, in the lung when compared with naïve and vehicle-treated mice. Mice deficient in 12/15-LOX (Alox15-/-) demonstrated better lung function, as measured by airway hyperresponsiveness (AHR), during fungal asthma. Histological assessment revealed reduced inflammation in the lungs of Alox15-/- mice compared with WT mice, which was corroborated by flow cytometric analysis of multiple myeloid (eosinophils and neutrophils) and lymphoid (CD4+ T and γδ T) cell populations. This was further supported by decreased levels of specific chemokines that promote the recruitment of these cells. Likewise, type 1 and 2, but not type 17 cytokines, were significantly lower in the lungs of Alox15-/- mice. Bone marrow chimera studies revealed that the presence of 12/15-LOX in hematopoietic cells contributed to AHR during fungal asthma. Taken together, our data support the hypothesis that hematopoietic-associated 12/15-LOX contributes to type 1 and 2 responses and exacerbation of allergic fungal asthma.NEW & NOTEWORTHY Humans with asthma sensitized to fungi often have more severe asthma than those who are not sensitized to fungi. Products of arachidonic acid generated via 5-lipoxygenase are often elevated in severe asthma and are successful FDA-approved drug targets. Less understood is the role of products generated via 12/15-lipoxygenase. We demonstrate that 12/15-lipoxygenase expression in hematopoietic cells contributes to type 1 and 2 responses and impaired lung function during allergic fungal asthma.

Neuroimmune Responses in a New Experimental Animal Model of Cerebral Aspergillosis.

Exposure of immunosuppressed individuals to the opportunistic fungal pathogen Aspergillus fumigatus may result in invasive pulmonary aspergillosis (IPA), which can lead to the development of cerebral aspergillosis (CA), a highly lethal infection localized in the central nervous system (CNS). There are no experimental models of CA that effectively mimic human disease, resulting in a considerable knowledge gap regarding mechanisms of neurological pathogenicity and neuroimmune responses during infection. In this report, immunosuppressed mice (via acute, high-dose corticosteroid administration) challenged with A. fumigatus resting conidia intranasally, followed a day later by a 70-fold lower inoculum of pre-swollen conidia intravenously (IN + IV + steroid), demonstrated increased weight loss, signs of severe clinical disease, increased fungal burden in the brain, and significant reduction in survival compared to immunosuppressed mice challenged intranasally only (IN + steroid) or non-immunosuppressed mice challenged both intranasally and intravenously (IN + IV). The IN + IV + steroid group demonstrated significant decreases in monocytes, eosinophils, dendritic cells (DCs), and invasive natural killer T (iNKT) cells, but not neutrophils or γδ T cells, in the brain compared to the IN + IV group. Likewise, the IN + IV + steroid group had significantly lower levels of interleukin (IL)-1ß, IL-6, IL-17A, CC motif chemokine ligand 3 (CCL3), CXC chemokine ligand 10 (CXCL10), and vascular endothelial growth factor (VEGF) in the brain compared to the IN + IV group. IN + IV + steroid was superior to both IN + IV + chemotherapy (cytarabine + daunorubicin) and IN + IV + neutropenia for the development of CA. In conclusion, we have developed a well-defined, physiologically relevant model of disseminated CA in corticosteroid-induced immunosuppressed mice with a primary pulmonary infection. This model will serve to advance understanding of disease mechanisms, identify immunopathogenic processes, and help define the protective neuroinflammatory response to CA. IMPORTANCE Invasive fungal infections (IFIs) result in significant mortality in immunosuppressed individuals. Of these, invasive pulmonary aspergillosis (IPA), caused by the opportunistic mold Aspergillus fumigatus, is the most lethal. Lethality in IPA is due to two main factors: destruction of the lung leading to compromised pulmonary function, and dissemination of the organism to extrapulmonary organs. Of these, the CNS is the most common site of dissemination. However, very little is known regarding the pathogenesis of or immune response during cerebral aspergillosis, which is directly due to the lack of an animal model that incorporates immunosuppression, lung infection, and consistent dissemination to the CNS/brain. In this report, we have developed a new experimental animal model of CA which includes the above parameters and characterized the neuroimmune response. We further compared this disseminated CA model to two additional immunosuppressive strategies. Overall, this model of disseminated CA following IPA in an immunosuppressed host provides a novel platform for studying the efficacy of antifungal drugs and immunotherapies for improving disease outcomes.