Patients with chronic granulomatous disease (CGD) have a mutated NADPH complex resulting in defective production of reactive oxygen species; these patients can develop severe colitis and are highly susceptible to invasive fungal infection. In NADPH oxidasedeficient mice, autophagy is defective but inflammasome activation is present despite lack of reactive oxygen species production. However, whether these processes are mutually regulated in CGD and whether defective autophagy is clinically relevant in patients with CGD is unknown. Here, we demonstrate that macrophages from CGD mice and blood monocytes from CGD patients display minimal recruitment of microtubule-associated protein 1 light chain 3 (LC3) to phagosomes. This defect in autophagy results in increased IL-1β release. Blocking IL-1 with the receptor antagonist (anakinra) decreases neutrophil recruitment and T helper 17 responses and protects CGD mice from colitis and also from invasive aspergillosis. In addition to decreased inflammasome activation, anakinra restored autophagy in CGD mice in vivo, with increased Aspergillus-induced LC3 recruitment and increased expression of autophagy genes. Anakinra also increased Aspergillus-induced LC3 recruitment from 23% to 51% (P < 0.01) in vitro in monocytes from CGD patients. The clinical relevance of these findings was assessed by treating CGD patients who had severe colitis with IL-1 receptor blockade using anakinra. Anakinra treatment resulted in a rapid and sustained improvement in colitis. Thus, inflammation in CGD is due to IL-1-dependent mechanisms, such as decreased autophagy and increased inflammasome activation, which are linked pathological conditions in CGD that can be restored by IL-1 receptor blockade.interleukin-1 | S. aureus | LPS | Crohn disease | autoinflammatory disease C hronic granulomatous disease (CGD) is an immunodeficiency characterized by defective production of reactive oxygen species (ROS) (1) due to mutations in the proteins forming the NADPH complex (2, 3). The most frequent form of CGD is hereditary and X-linked, and is caused by a mutation in the gene CYBB, which encodes the protein gp91 phox , the catalytic subunit of the NADPH oxidase complex. In autosomal and recessive forms of CGD, the mutations affect the genes encoding p22 , which are all part of the NADPH complex, resulting in a defective NADPH oxidase complex. As a result, patients who have CGD have defective microbial killing by phagocytic cells and an increased susceptibility to infections, especially Staphylococcus aureus and Aspergillus spp. (4, 5). Paradoxically, ROS deficiency in patients with CGD results in a hyperinflammatory state (6), and one-third of the patients develop an inflammatory colitis indistinguishable from Crohn disease (7-10).The hyperinflammatory state in CGD is linked to inflammasome activation (11-13). Studies in mice and humans reveal that autophagy is crucial for IL-1β transcription (14) and processing of pro-IL-1β (15, 16); defects in autophagy result in increased secretion of IL-1β. ROS product...

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.

This study provides a link between tryptophan catabolism and lung immune homeostasis in murine CF, representing a proof-of-concept that targeting pathogenic inflammation via IDO-mimetic drugs may benefit patients with CF.