Dysregulated inflammasome activation contributes to respiratory infections and pathologic airway inflammation. Through basic and translational approaches involving murine models and human genetic epidemiology, we show here the importance of the different inflammasomes in regulating inflammatory responses in mice and humans with cystic fibrosis (CF), a life-threatening disorder of the lungs and digestive system. While both contributing to pathogen clearance, NLRP3 more than NLRC4 contributes to deleterious inflammatory responses in CF and correlates with defective NLRC4-dependent IL-1Ra production. Disease susceptibility in mice and microbial colonization in humans occurrs in conditions of genetic deficiency of NLRC4 or IL-1Ra and can be rescued by administration of the recombinant IL-1Ra, anakinra. These results indicate that pathogenic NLRP3 activity in CF could be negatively regulated by IL-1Ra and provide a proof-of-concept evidence that inflammasomes are potential targets to limit the pathological consequences of microbial colonization in CF.

The progress in human disease treatment can be greatly advanced through the implementation of nanomedicine. This approach involves targeted and cell-specific therapy, controlled drug release, personalized dosage forms, wearable drug delivery, and companion diagnostics. By integrating cutting-edge technologies with drug delivery systems, greater precision can be achieved at the tissue and cellular levels through the use of stimuli-responsive nanoparticles, and the development of electrochemical sensor systems. This precision targeting - by virtue of nanotechnology - allows for therapy to be directed specifically to affected tissues while greatly reducing side effects on healthy tissues. As such, nanomedicine has the potential to transform the treatment of conditions such as cancer, genetic diseases, and chronic illnesses by facilitating precise and cell-specific drug delivery. Additionally, personalized dosage forms and wearable devices offer the ability to tailor treatment to the unique needs of each patient, thereby increasing therapeutic effectiveness and compliance. Companion diagnostics further enable efficient monitoring of treatment response, enabling customized adjustments to the treatment plan. The question of whether all the potential therapeutic approaches outlined here are viable alternatives to current treatments is also discussed. In general, the application of nanotechnology in the field of biomedicine may provide a strong alternative to existing treatments for several reasons. In this review, we aim to present evidence that, although in early stages, fully merging advanced technology with innovative drug delivery shows promise for successful implementation across various disease areas, including cancer and genetic or chronic diseases.

Since IL-37 transgenic mice possesses broad anti-inflammatory properties, we assessed whether recombinant IL-37 affects inflammation in a murine model of invasive pulmonary aspergillosis. Recombinant human IL-37 was injected intraperitoneally into mice prior to infection and the effects on lung inflammation and inflammasome activation were evaluated. IL-37 markedly reduced NLRP3-dependent neutrophil recruitment and steady state mRNA levels of IL-1β production and mitigated lung inflammation and damage in a relevant clinical model, namely aspergillosis in mice with cystic fibrosis. The anti-inflammatory activity of IL-37 requires the IL-1 family decoy receptor TIR-8/SIGIRR. Thus, by preventing activation of the NLRP3 inflammasome and reducing IL-1β secretion, IL-37 functions as a broad spectrum inhibitor of the innate response to infection-mediated inflammation, and could be considered to be therapeutic in reducing the pulmonary damage due to non-resolving Aspergillus infection and disease. IL-37, firstly identified by in silico research in the year 2000, is a member of the IL-1 family. The biological properties of IL-37 are mainly those of down-regulating inflammation in models of septic shock, chemical colitis, cardiac ischemia and contact dermatitis. Whether and how IL-37 down-regulates the inflammation of infection, and its consequences, is not known. We observed that IL-37 limits inflammation and disease severity in murine invasive aspergillosis, an infection model in which cytokines of the IL-1 family have important roles. However, given that IL-1R1-deficient or caspase 1-deficient mice are resistant to lung inflammation during infection and that IL-1 signaling could drive the differentiation of antifungal inflammatory Th17 cells, the pro-inflammatory properties of IL 1-induced inflammation in aspergillosis is potentially dangerous for the host. IL-37 markedly reduced NLRP3-dependent neutrophil recruitment and steady state mRNA levels of IL-1β production and mitigated lung inflammation and damage in a relevant clinical model, namely aspergillosis in mice with cystic fibrosis. The anti-inflammatory activity of IL-37 requires the IL-1 receptor family decoy TIR-8/SIGIRR. Thus, IL-37 functions as a broad spectrum inhibitor of infection-mediated inflammation, and could be considered to be therapeutic in reducing the pulmonary damage due to non-resolving Aspergillus infection and disease.

T helper 9 (Th9) cells contribute to lung inflammation and allergy as sources of interleukin-9 (IL-9). However, the mechanisms by which IL-9/Th9 mediate immunopathology in the lung are unknown. Here we report an IL-9-driven positive feedback loop that reinforces allergic inflammation. We show that IL-9 increases IL-2 production by mast cells, which leads to expansion of CD25⁺type 2 innate lymphoid cells (ILC2) and subsequent activation of Th9 cells. Blocking IL-9 or inhibiting CD117 (c-Kit) signalling counteracts the pathogenic effect of the described IL-9-mast cell-IL-2 signalling axis. Overproduction of IL-9 is observed in expectorates from cystic fibrosis (CF) patients, and a sex-specific variant of IL-9 is predictive of allergic reactions in female patients. Our results suggest that blocking IL-9 may be a therapeutic strategy to ameliorate inflammation associated with microbial colonization in the lung, and offers a plausible explanation for gender differences in clinical outcomes of patients with CF.

Vaginal infections with Candida spp. frequently occur in women of childbearing age. A small proportion of these women experience recurrent vulvovaginal candidosis (RVVC), which is characterized by at least three episodes of infection in one year. In addition to known risk factors such as antibiotics, diabetes, or pregnancy, host genetic variation and inflammatory pathways such as the IL-1/Th17 axis have been reported to play a substantial role in the pathogenesis of RVVC. In this study, we assessed a variable number tandem repeat (VNTR) polymorphism in the NLRP3 gene that encodes a component of the inflammasome, processing the proinflammatory cytokines IL-1β and IL-18. A total of 270 RVVC patients and 583 healthy controls were analyzed, and increased diseases susceptibility was associated with the presence of the 12/9 genotype. Furthermore, functional studies demonstrate that IL-1β production at the vaginal surface is higher in RVVC patients bearing the 12/9 genotype compared to controls, whereas IL-1Ra levels were decreased and IL-18 levels remained unchanged. These findings suggest that IL-1β-mediated hyperinflammation conveyed by the NLRP3 gene plays a causal role in the pathogenesis of RVVC and may identify this pathway as a potential therapeutic target in the disease.