Abstract Aspergillus fumigatus is associated with allergic bronchopulmonary aspergillosis, a pulmonary allergic disorder, in which neutrophilia predicts a poor outcome. In our efforts to recapitulate fungus-induced airway neutrophilia in the allergic setting, we found that similar exposure to the fungus resulted in a neutrophil-dominated response in BALB/c mice but an eosinophil-biased response in C57BL/6 mice. By performing a comparative study, we identified TNF-α as the key mediator that skewed the response towards neutrophilia but away from eosinophilia. Between the two strains, TNF-αhigh CD11b+ Ly6C+ DCs were more abundant in the lungs of WT BALB/c mice which was compromised in MyD88-/-, dectin-1-/- and TNF-α-/- mice. As compared to TNF-αhigh Balb/c-DCs, TNF-αlow C57BL/6-DCs contained more NF-B p50 homodimers as strong repressors of TNF-α transcription. Lower TNF-α accounted for lower TLR2 levels on C57BL/6 DCs impairing collaboration between TLR2 and Dectin-1 in augmenting TNF-α via a positive feedback loop. Functionally, in Balb/c mice, the high level of TNF-α enhanced Th17 responses and in collaboration with IL-17A upregulated the neutrophil chemoattractants KC and MIP-2. Conversely, the lungs of C57BL/6 or TNF-α-/- mice showed higher IL-5 levels and therefore an eosinophil-rich response. Our study for the first time highlights a central role of TNF-α as a molecular switch that regulates the neutrophil/eosinophil balance in airway inflammation.
Females are more susceptible to development of asthma than are males. In a mouse model of ovalbumin-induced airway inflammation, with aggravated disease in females compared with males, we studied interactions between immune and resident lung cells during asthma development to elucidate which processes are affected by sex. We studied numbers of regulatory T cells (Tregs), effector T cells, myeloid dendritic cells (mDCs), and alternatively activated macrophages (AAMPhi), and their functional capabilities. Male and female mice had comparable Treg numbers in lung tissue and comparable Treg function, but effector T cells had expanded to a greater extent in lungs of females after ovalbumin exposure. This difference in T cell expansion was therefore not the result of lack of Treg control, but appeared to be driven by a greater number of inflammatory mDCs migrating from the lungs to lymph nodes in females. Resident lung cells can influence mDC migration, and AAMPhi in lung tissue were found to be involved. Artificially elevating the number of AAMPhi in lung tissue increased the migration of mDCs and airway inflammation. We found greater numbers of AAMPhi in female lungs than in males; we therefore postulate that AAMPhi are involved in increased airway inflammation found in female mice.
Aspergillus fumigatus (A. fumigatus) is a fungus that induces allergic airways diseases in immunocompromised patients, and in patients with cystic fibrosis or severe asthma. Host defense against this fungus depends on both innate and adaptive immunity. DCs have been shown to transport conidia or hyphae from the airway to the lung draining lymph node and initiate T cell responses. Fungus‐induced Th2 response has been associated with allergic bronchopulmonary aspergillosis while Th1 response favors resistance to the pathogen. We have initiated studies to understand adaptive immune responses against A. fumigatus. We have found that resting conidia are not able to induce activation of bone marrow derived‐DCs, while swollen conidia efficiently promote DC maturation. In order to investigate how Aspergillus‐programmed DCs prime T cell responses, we cocultured fungus‐exposed DCs with CD4+ T cells in the presence or absence of TCR activation by specific antigen or anti‐CD3 antibody. Even without TCR signaling, similar to DCs exposed to the dectin‐1 agonist curdlan, Aspergillus‐conditioned DCs induced IL‐17 from T cells, which was not elicited by control DCs that were not exposed to any stimuli. Collectively, our observations show the ability of Aspergillus to prime DCs for IL‐17 production from CD4+ T cells, which is increasingly being associated with allergic diseases. Funded by: HL84932 and HL 77430 (to A.R.)
Although asthma has long been considered a heterogeneous disease, attempts to define subgroups of asthma have been limited. In recent years, both clinical and statistical approaches have been utilized to better merge clinical characteristics, biology, and genetics. These combined characteristics have been used to define phenotypes of asthma, the observable characteristics of a patient determined by the interaction of genes and environment. Identification of consistent clinical phenotypes has now been reported across studies. Now the addition of various 'omics and identification of specific molecular pathways have moved the concept of clinical phenotypes toward the concept of molecular phenotypes. The importance of these molecular phenotypes is being confirmed through the integration of molecularly targeted biological therapies. Thus the global term asthma is poised to become obsolete, being replaced by terms that more specifically identify the pathology associated with the disease.
Indoleamine 2,3 dioxgenase (IDO) has been shown to inhibit Th1‐mediated immune responses. However, the role of IDO in Th2 cell‐mediated diseases has not been adequately addressed. We have investigated the role of IDO in allergic airways disease. Interestingly, IDO protein expression was easily detected in lung myeloid DCs from naïve wild‐type (WT) mice which was not true for spleen DCs. Upon antigen sensitization via the lung, fewer mature DCs and fewer adoptively transferred CD4+ T cells from DO11.10 mice were recovered from lung‐draining lymph nodes (LNs) of IDO−/− mice compared to that from LNs of WT mice. In line with the lower net accumulation of adoptively transferred CD4+ T cells in the lung‐draining LNs of IDO−/− mice, Th2 cytokine levels in the lung tissue of these mice was also lower. In a chronic model of experimental asthma, all features of allergic airways disease were significantly attenuated in the IDO−/− mice. Collectively, these data show an important role for IDO in lung myeloid DC activation in response to allergens and suggest that the reduced Th2 type immune response in IDO−/− mice is due, at least in part, to less effective co‐stimulation between DCs and T cells. Supported by NIH grants HL 77430 (to A.R) and HL60207 (to P.R.)
Immune tolerance to allergens in early-life decreases the risk for asthma in later life. Here we show establishment of stable airway tolerance to the allergen, house dust mite (HDM), by exposing newborn mice repeatedly to a low dose of the allergen. Lung dendritic cells (DCs) from tolerized mice induced a low Th2 response in vitro mirroring impact of tolerance in vivo. In line with our previous finding of increased mitochondrial H2O2 production from lung DCs of mice tolerized to ovalbumin, depletion of mitochondrial H2O2 in MCAT mice abrogated HDM-induced airway tolerance (Tol) with elevated Th2 effector response, airway eosinophilia, and increased airway hyperreactivity. WT-Tol mice displayed a decrease in total, cDC1 and cDC2 subsets in the lung as compared to that in naive mice. In contrast, the lungs of MCAT-Tol mice showed 3-fold higher numbers of cDCs including those of the subsets as compared to that in WT mice. Our study demonstrates an important role of mitochondrial H2O2 in constraining lung DC numbers towards establishment of early-life airway tolerance to allergens.
