Asthma-associated bacterial infections: Are they protective or deleterious?

Eosinophilic, noneosinophilic, or mixed granulocytic inflammations are the hallmarks of asthma heterogeneity. Depending on the priming of lung immune and structural cells, subjects with asthma might generate immune responses that are TH2-prone or TH17-prone immune response. Bacterial infections caused by Haemophilus, Moraxella, or Streptococcus spp. induce the secretion of IL-17, which in turn recruit neutrophils into the airways. Clinical studies and experimental models of asthma indicated that neutrophil infiltration induces a specific phenotype of asthma, characterized by an impaired response to corticosteroid treatment. The understanding of pathways that regulate the TH17-neutrophils axis is critical to delineate and develop host-directed therapies that might control asthma and its exacerbation episodes that course with infectious comorbidities. In this review, we outline clinical and experimental studies on the role of airway epithelial cells, S100A9, and high mobility group box 1, which act in concert with the IL-17-neutrophil axis activated by bacterial infections, and are related with asthma that is difficult to treat. Furthermore, we report critically our view in the light of these findings in an attempt to stimulate further investigations and development of immunotherapies for the control of severe asthma.

IL-22 Is Deleterious along with IL-17 in Allergic Asthma but Is Not Detrimental in the Comorbidity Asthma and Acute Pneumonia.

There is evidence that IL-22 and IL-17 participate in the pathogenesis of allergic asthma. To investigate the role of IL-22, we used IL-22 deficient mice (IL-22 KO) sensitized and challenged with ovalbumin (OVA) and compared with wild type (WT) animals exposed to OVA. IL-22 KO animals exposed to OVA showed a decreased number and frequency of eosinophils, IL-5 and IL-13 in the airways, reduced mucus production and pulmonary inflammation. In addition, IL-22 KO animals exhibited a decreased percentage and number of lung CD11c+CD11b+ cells and increased apoptosis of eosinophils. Th17 cell transfer generated from IL-22 KO to animals previously sensitized and challenged with OVA caused a reduction in eosinophil frequency and number in the airways compared to animals transferred with Th17 cells generated from WT mice. Therefore, IL-22 is deleterious with concomitant secretion of IL-17. Our findings show a pro-inflammatory role for IL-22, confirmed in a model of allergen-free and allergen-specific immunotherapy. Moreover, during the comorbidity asthma and pneumonia that induces neutrophil inflammation, IL-22 was not detrimental. Our results show that targeting IL-22 would negatively affect the survival of eosinophils, reduce the expansion or migration of CD11c+CD11b+ cells, and negatively regulate allergic asthma.

Aspergillus fumigatus Extracellular Vesicles Display Increased Galleria mellonella Survival but Partial Pro-Inflammatory Response by Macrophages.

Fungal extracellular vesicles (EVs) mediate intra- and interspecies communication and are critical in host-fungus interaction, modulating inflammation and immune responses. In this study, we evaluated the in vitro pro- and anti-inflammatory properties of Aspergillus fumigatus EVs over innate leukocytes. A. fumigatus EVs induced a partial proinflammatory response by macrophages, characterized by increased tumor necrosis factor-alpha production, and increased gene expression of induced nitric oxide synthase and adhesion molecules. EVs induce neither NETosis in human neutrophils nor cytokine secretion by peripheral mononuclear cells. However, prior inoculation of A. fumigatus EVs in Galleria mellonella larvae resulted in increased survival after the fungal challenge. Taken together, these findings show that A. fumigatus EVs play a role in protection against fungal infection, although they induce a partial pro-inflammatory response.

Artepillin C Reduces Allergic Airway Inflammation by Induction of Monocytic Myeloid-Derived Suppressor Cells.

Propolis is a natural product produced by bees that is primarily used in complementary and alternative medicine and has anti-inflammatory, antibacterial, antiviral, and antitumoral biological properties. Some studies have reported the beneficial effects of propolis in models of allergic asthma. In a previous study, our group showed that green propolis treatment reduced airway inflammation and mucus secretion in an ovalbumin (OVA)-induced asthma model and resulted in increased regulatory T cells (Treg) and polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) frequencies in the lungs, two leukocyte populations that have immunosuppressive functions. In this study, we evaluated the anti-inflammatory effects of artepillin C (ArtC), the major compound of green propolis, in the context of allergic airway inflammation. Our results show that ArtC induces in vitro differentiation of Treg cells and monocytic MDSC (M-MDSC). Furthermore, in an OVA-induced asthma model, ArtC treatment reduced pulmonary inflammation, eosinophil influx to the airways, mucus and IL-5 secretion along with increased frequency of M-MDSC, but not Treg cells, in the lungs. Using an adoptive transfer model, we confirmed that the effect of ArtC in the reduction in airway inflammation was dependent on M-MDSC. Altogether, our data show that ArtC exhibits an anti-inflammatory effect and might be an adjuvant therapy for allergic asthma.