Interleukin-23-Mediated Inflammation in Pseudomonas aeruginosa Pulmonary Infection

Abstract

Pseudomonas aeruginosa is an opportunistic pathogen that is capable of causing acute and chronic pulmonary infection in the immunocompromised host. In the case of cystic fibrosis (CF), chronic P. aeruginosa infection causes increased mortality by promoting overly exuberant airway inflammation and cumulative lung damage. Identifying the key regulators of this inflammation may lead to the development of new therapies that improve P. aeruginosa-related mortality. We report here that interleukin-23 (IL-23), the cytokine most clearly tied to IL-17-mediated inflammation, also promotes IL-17-independent inflammation during P. aeruginosa pulmonary infection. During the early innate immune response, prior to IL-17 induction, IL-23 acts synergistically with IL-1␤ to promote early neutrophil (polymorphonuclear leukocyte [PMN]) recruitment. However, at later time points, IL-23 also promoted IL-17 production by lung ␥␦ T cells, which was greatly augmented in the presence of IL-1␤. These studies show that IL-23 controls two independent phases of neutrophil recruitment in response to P. aeruginosa infection: early PMN emigration that is IL-17 independent and later PMN emigration regulated by IL-17. Pseudomonas aeruginosa pulmonary infection occurs in immunocompromised hosts and is associated with significant morbidity and mortality. The pathogen induces a robust neutrophil response that causes significant airway damage and does not always eliminate the pathogen. In cystic fibrosis (CF), where infection is chronic, the inflammation causes cumulative airway damage that is a major contributor to morbidity and mortality (41,46,62). Identifying the immune mediators that promote this inflammation is the first step in developing new therapies that can improve outcomes in chronic P. aeruginosa pulmonary infection.We and others have previously shown that airway interleukin-23 (IL-23) and IL-17 levels correlate with infection status and inflammation in individuals with CF (12,15,38) and that lymphocytes from CF-derived draining lymph nodes produce higher levels of IL-17 than non-CF disease controls (3). We have also shown that both IL-23 and IL-17 are critical for neutrophil recruitment in a murine model of chronic P. aeruginosa pulmonary infection (14). While these data demonstrate that the IL-23/ IL-17 proinflammatory axis is active during P. aeruginosa airway infection and in CF, the studies did not isolate the actions of IL-23 from those of IL-17.Historically, IL-17 has been credited with promoting both neutrophil recruitment and granulopoiesis through its induction of neutrophil growth factors and chemokines, including IL-6, granulocyte colony-stimulating factor (G-CSF), keratinocyte chemoattractant (KC), and macrophage inflammatory protein 2 (MIP-2) (14,24,30,38,49,54,64). IL-23, a recently identified IL-12 family member (42, 60), has been primarily characterized in the context of this Th17 response (1,25,33). Of note, however, IL-23-overexpressing mice have a hyperinflammatory phenotype and notable elevations in serum IL-1␤ and t...

Activation of inflammasome signaling mediates pathology of acute P. aeruginosa pneumonia

“…Murine epithelial cells were found to produce IL-1β in response to both WT and fliC PAK; hence, other effectors, such as type III secretion system components or pili, may be involved in epithelial signaling (16,19,36,(56)(57)(58). This hypothesis is supported by a recent study in which P. aeruginosa lacking the type III secretion system stimulated less caspase-1 activation, IL-1β secretion, and neutrophil recruitment after only 4 hours of infection (37)(38)(39)(40)(41)59). The contribution of the NLRC4 inflammasome in stromal cells as well as AMs was previously shown to be important for P. aeruginosa clearance, although this was in mice with a different genetic background (19,60).…”

“…Importantly, AM depletion did not alter levels of IL-1Ra, an endogenous inhibitor of IL-1β. The participation of IL-6 and IL-17 in the host response to extracellular pathogens has been well established (37)(38)(39)(40)(41). There were similar numbers of CD11c -CD4 + cells in BAL of clodronate-treated animals; however, fewer of these were IL-17 + , correlating with substantially decreased phospho- Inhibition of the NLRC4 inflammasome improves clearance of P. aeruginosa.…”

Flagellin Induces Myeloid-Derived Suppressor Cells: Implications for Pseudomonas aeruginosa Infection in Cystic Fibrosis Lung Disease

“…Previous studies have characterized the T cell response in human CF patients (33,34) (24,26,27,30) (35) and murine P. aeruginosa (36)(37)(38)(39)(40) or Aspergillus fumigatus infection models (41)(42)(43), providing evidence that the adaptive T cell response in CF is altered at several levels. CF T cells were found to be prone to a Th2 phenotype, with the CFTR mutation itself and/or chronic infections with P. aeruginosa as possible underlying factors (42,(44)(45)(46).…”

Ethanol Impairs Mucosal Immunity against Streptococcus pneumoniae Infection by Disrupting Interleukin 17 Gene Expression

“…The ethanol group demonstrated higher bacterial burdens and decreased IL-17 related pulmonary chemokine responses after bacterial challenge. Surprisingly, neither recombinant IL-17 nor IL-23 plus IL1B, which can activate ␥␦ T cells to produce IL-17 (15), improved bacterial clearance in ethanol-treated mice. However, recombinant CXCL1 and CXCL5 but not CXCL2 decreased S. pneumoniae burden in the ethanol group to close to control levels.…”

“…Since IL-17 and related genes were downregulated in the lung tissue of ethanol-treated mice, we examined if rescuing with recombinant IL-17 in the lungs would decrease bacterial burden in these animals. To restore IL-17 to a physiologically relevant concentration, we gave the ethanol-treated mice recombinant IL-23 and IL-1B, which are known to induce IL-17 production mostly by ␥␦ T cells in the lung (15), or recombinant IL-17. There was no change in bacterial clearance (Fig.…”