Immunomodulation of Airway Epithelium Cell Activation by Mesenchymal Stromal Cells Ameliorates House Dust Mite–Induced Airway Inflammation in Mice

Abstract

Allergic asthma is underpinned by T helper 2 (Th2) inflammation. Redundancy in Th2 cytokine function and production by innate and adaptive immune cells suggests that strategies aimed at immunomodulation may prove more beneficial. Hence, we sought to determine whether administration of mesenchymal stromal cells (MSCs) to house dust mite (HDM) (Dermatophagoides pteronyssinus)-sensitized mice would suppress the development of Th2 inflammation and airway hyperresponsiveness (AHR) after HDM challenge. We report that the intravenous administration of allogeneic donor MSCs 1 hour before allergen challenge significantly attenuated the features of allergic asthma, including tissue eosinophilia, Th2 cytokine (IL-5 and IL-13) levels in bronchoalveolar lavage fluid, and AHR. The number of infiltrating type 2 innate lymphoid cells was not affected by MSC transfer, suggesting that MSCs may modulate the adaptive arm of Th2 immunity. The effect of MSC administration was long lasting; all features of allergic airway disease were significantly suppressed in response to a second round of HDM challenge 4 weeks after MSC administration. Further, we observed that MSCs decreased the release of epithelial cell-derived alarmins IL-1α and high mobility group box-1 in an IL-1 receptor antagonist-dependent manner. This significantly decreased the expression of the pro-Th2 cytokine IL-25 and reduced the number of activated and antigen-acquiring CD11c(+)CD11b(+) dendritic cells in the lung and mediastinal lymph nodes. Our findings suggest that MSC administration can ameliorate allergic airway inflammation by blunting the amplification of epithelial-derived inflammatory cytokines induced by HDM exposure and may offer long-term protection against Th2-mediated allergic airway inflammation and AHR.

Aryl Hydrocarbon Receptor Protects Lungs from Cockroach Allergen–Induced Inflammation by Modulating Mesenchymal Stem Cells

“…MSCs have been shown to ameliorate allergic airway inflammation in mouse models of asthma (58–60). Thus, it is likely that the exacerbated inflammation in AhR −/− mice may be due to the insufficient number of MSCs present in the lungs.…”

“…MSCs have a remarkable capacity to modulate immune responses and change the progression of different inflammatory diseases through the release of a variety of bioactive molecules (77–79). Recent studies have suggested that MSCs ameliorate allergic airway inflammation in mouse models of asthma (58–60). This study illustrated that MSCs were decreased in CRE-challenged AhR −/− mice with exacerbated lung inflammation, but increased in TCDD-treated CRE-challenged mice with ameliorated lung inflammation.…”

Barrier Epithelial Cells and the Control of Type 2 Immunity

“…Neutralization of IL-1a or HMGB1 is able to block production of the pro-Th2-cell-derived cytokines IL-33, IL-25, and GM-CSF in the lung after HDM administration, showing that the epithelial alarmins act very upstream in the allergic type 2 cascade Ullah et al, 2014;Willart et al, 2012). Adoptive transfer of mesenchymal stem cells has been shown to suppress features of asthma, via interleukin-1 receptor antagonist (IL-1RA)-mediated suppression of IL-1a and HMGB1 (Duong et al, 2015). Increased amounts of HMGB1 are found in the skin of mice with AD lesions (Karuppagounder et al, 2014(Karuppagounder et al, , 2015.…”

Therapeutic administration of bone marrow‐derived mesenchymal stromal cells reduces airway inflammation without up‐regulating Tregs in experimental asthma

“…increased TGF-b levels seem to mobilize more MSCs to the airways, demonstrating how allergen's particularities influence MSCs in vivo 37. In HDM model, epithelial activation by proteases exacerbate lung inflammation, nevertheless, MSC administered prophylactically still prevents asthma by modulating epithelial cells 38,39. The obstacles for cell therapy seem to be highlighted when established asthma models are improved using relevant allergens.…”