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Chronic pulmonary aspergillosis (CPA) is a devastating disease with increasing prevalence worldwide. The characteristic granulomatous-like inflammation poses as the major setback to effective antifungal therapies by limiting drug access to fungi. These inflammatory lung structures are reported to be severely hypoxic; nevertheless, the underlying mechanisms whereby these processes contribute to fungal persistence remain largely unknown. Hypoxia-inducible factor 1 alpha (HIF-1α), besides being the major cellular response regulator to hypoxia, is a known central immune modulator. Here, we used a model of Aspergillus fumigatus airway infection in myeloid-restricted HIF-1α knock-out (mHif1α-/-) mice to replicate the complex structures resembling fungal granulomas and evaluate the contribution of HIF-1α to antifungal immunity and disease development. We found that fungal-elicited granulomas in mHif1α-/- mice had significantly smaller areas, along with extensive hyphal growth and increased lung fungal burden. This phenotype was associated with defective neutrophil recruitment and an increased neutrophil death, therefore highlighting a central role for HIF-1α-mediated regulation of neutrophil function in the pathogenesis of chronic fungal infection. These results hold the promise of an improved capacity to manage the progression of chronic fungal disease and open new avenues for additional therapeutic targets and niches of intervention.

Pulmonary fibrosis (PF) is the end pathologic stage of several interstitial lung diseases associated with high morbidity and mortality rates. However, the treatments used in clinical practice are only capable to slow the disease progression rather than stop it. Evidences have shown critical roles of chronic inflammation in the progression of PF-associated diseases. However, the drivers of these effects are still unknown. Therefore, new insights about the immune regulation of PF are fundamental to develop more efficient therapeutic approaches. Growing evidences have shown the role of hepatocyte growth factor (HGF) and its receptor (c-Met) in modulation of immune cell’s migratory capacity and functions, namely its upon inflammatory stimuli and required for extravasation of neutrophil to inflamed tumours. Nevertheless, the effects of this signalling in immune cells in the context of PF-associated lung diseases remains unexplored. Therefore, we used a bleomycin‑induced PF model to understand the contribution of c‑Met‑expressing immune cells to PF progression. Interestingly, our data demonstrate that inflammatory cells and c-Met expression induction was specially observed on T cells and interstitial macrophages. Furthermore, in a cell‑specific transgenic mouse, in which c-Met was deleted in hematopoietic and endothelial cells, c-Met expression correlated with an increment in inflammatory infiltration, namely neutrophils and interstitial macrophages, and reduction of proinflammatory cytokines, along with higher tissue destruction and collagen deposition. Thus, our findings point out HGF/c‑Met signalling as a critical player in the pathogenesis of PF, probably through immune cells.