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

Abstract

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 T_H2-prone or T_H17-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 T_H17-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.

Keywords: IL-17; Severe asthma; bacterial infections; lung inflammation; neutrophil.

FIG 1

Immunopathology of allergic asthma. Inhaled allergens activate AECs that recruit and activate DCs and ILC2s by production of IL-25, IL-33, TSLP, ATP, uric acid, LPA, and ROS. DCs and ILC2s induce T_H2 differentiation and activation. T_H9 and T_H17 might also undergo differentiation. Eosinophil (EΦ) recruitment and activation followed by activation of T_H2, T_H9, and T_H17 promote AHR and mucus production, AEC damage, and AHR. ILC2, Type 2 innate lymphoid cell; LPA, lysophosphatidic acid; ROS, reactive oxygen species; TSLP, thymic stromal lymphopoetin.

FIG 2

Immunopathology of severe asthma. Allergens, pollutants, and viral/bacterial infections promote the activation of AECs that recruit and activate DCs by production of IL-1β, IL-6, CXCL8, CCL2, and CCL20. DCs migrate to draining lymph node (dLN) and induce T_H1, T_H2, and T_H17 cell differentiation. ILC3s provide the early sources of IL-17 and IL-22. ILC3, T_H17, and T_H1 contribute to recruit neutrophils (NΦ). NΦ cause epithelial damage by release of NETs. AEC-derived signals (S100A9, CXCL1, CXCL2, and CXCL8) stimulate the NΦ survival and recruitment, respectively. The interface of neutrophils and AECs amplifies the local inflammation and aggravates asthma immunopathology. ILC3, Type 3 innate lymphoid cell.

FIG 3

Bacterial infections and asthma exacerbation. Bacterial infections activate TLRs on DCs and might drive the allergic immune response from T_H2 to T_H2/T_H17 cells. Activated eosinophils and neutrophils produce inflammatory mediators that activate smooth muscle cells and damage epithelial cells, which release S100A8 and S100A9 alarmins. T_H17 cells might indirectly aggravate the immunopathology of asthma, inducing the recruitment of neutrophils that produce NETs.