Mesenchymal Stromal Cells Mediate Aspergillus Hyphal Extract-Induced Allergic Airway Inflammation by Inhibition of the Th17 Signaling Pathway

Abstract

Systemic administration of mesenchymal stromal cells (MSCs) suppresses airway inflammation and methacholine-induced airway hyper-responsiveness (AHR) in mouse models of T helper cell (Th) type 2-mediated eosinophilic allergic airway inflammation (AAI); however, the efficacy of MSCs in mouse models of severe Th17-mediated neutrophilic AAI has not yet been demonstrated. We assessed MSC effects in a mouse model of mixed Th2/Th17 AAI produced by mucosal exposure to Aspergillus fumigatus hyphal extract (AHE). Following sensitization produced by oropharyngeal AHE administration, systemic (tail vein) administration of syngeneic MSCs on the first day of challenge significantly reduced acute AHR predominantly through reduction of Th17-mediated airway inflammation. In parallel experiments, MSCs also mitigated AHR when administered during recurrent challenge 10 weeks after initial sensitization and challenge through reduction in systemic Th17-mediated inflammation. Investigation into potential mechanistic actions of MSCs in this model demonstrated that although T regulatory cells were increased in all AHE-treated mice, MSC administration did not alter T regulatory cell numbers in either the acute or recurrent model. Differential induction of interleukin-17a secretion was observed in ex vivo restimulation of mediastinal lymph node mixed-cell cytokine analyses. Although the mechanisms by which MSCs act to decrease inflammation and AHR in this model are not yet fully elucidated, decrease in Th17-mediated airway inflammation appears to play a significant role. These results provide a basis for further investigations of MSC administration as a potential therapeutic approach for severe refractory neutrophilic asthma. STEM CELLS TRANSLATIONAL MEDICINE 2014;3:194-205

Stem cells in animal asthma models: a systematic review

“…The most common allergen used was ovalbumin (15 studies), with other studies that used ragweed [9], toluene diisocyanate [10], house-dust mite [11,12], aspergillus fungal extract [13] and cockroach extract [11]. The studies varied in duration, up to 118 days [14].…”

“…However, treatment with MSCs before sensitization did decrease BAL total cell count in the Kavanagh [25] and Goodwin [20] studies. The other exception was the recurrent inflammation group in the Lathrop [13] study [13]. This study used Aspergillus fungal extract to induce Th17 airway inflammation rather than Th2.…”

Human Mesenchymal Stem Cells Resolve Airway Inflammation, Hyperreactivity, and Histopathology in a Mouse Model of Occupational Asthma

“…Recent reports have demonstrated the anti-inflammatory potential of MSCs in several murine asthma models induced by high-molecular-weight allergens (ovalbumin, ragweed, and aspergillus hyphal extract) [11,13,[22][23][24][25][26][27][28] and in a low-molecular-weight, toluene diisocyanate (TDI)-induced asthma model [14]. However, in most of these models, the MSCs were administered preventively, that is, during the immunization phase or concomitantly with the induction of asthma.…”

“…IL-6 has recently emerged as main regulator of the differentiation and function of Th17 cells [33]. Thus, further research is needed to confirm the occurrence of Th17-driven airway inflammation in our AP-induced neutrophilic asthma model and its therapeutic reduction by hASCs, analogously to other recently reported Th17-driven neutrophilic asthma models [28].…”

Mesenchymal stem cells and infectious diseases: Smarter than drugs

“…provided an important addition to our understanding of anti-asthma properties of MSCs. Although not a direct anti-fungal effect, MSCs were efficacious in a mouse model of an Aspergillus fumigatus hyphal extract-triggered neutrophilmediated allergic airway inflammation, largely by inhibiting Th17 responses [64].…”