The type 1 and type 3 immune responses underlying the tissue inflammation associated with NOX2 deficiency.

Phagocytic nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (NOX2) is the primary source of reactive oxygen species (ROS) in leukocytes for host defense and immune signaling. Loss-of-function mutations in NOX2 leads to chronic granulomatous disease, a life-threatening immunodeficient disorder with defective phagocyte function to produce ROS for killing bacteria and fungi. NOX2, however, is not restricted to phagocytic leukocytes; it is also present in various immune cell types, with expression levels varying among them. Disrupted redox balance in CGD patients predisposes them to develop Th1/Th17-type (type 1 and type 3) inflammation leading to severe tissue inflammation in organs including joints, lungs, heart and kidneys. The high Th1 cytokines in tissues induce macrophage and T cell activation, which makes a positive feedback loop to recruit more immune cells to facilitate the granuloma formation in CGD patients. Moreover, IFN-γ has been shown to play a critical role in age-associated B cells (ABC) differentiation by inducing T-bet expression through STAT1 activation in B cells and elevated autoantibody production. The data suggested that the IFN-γ-rich Th1 environment resulting from NOX2 deficiency may promote ABC differentiation via the IFN-STAT axis. Previous studies showed that CGD patients and NOX2 deficient mice have stronger Th17 type inflammation and higher type 3 effector cytokine production. Overexpression of IL-1β following NLRP3 inflammasome-dependent or -independent activation aggravates Th17 hyperinflammation in CGD patients, who are prone to develop comorbidities including pulmonary fibrosis, arthritis, lupus-like nephritis and increased risk of cardiovascular diseases. In this review, we summarize the pivotal role of NOX2 in the balance of redox homeostasis and its relationship with type 1/type 3 inflammation. The key issues to be explored on NOX2-deficiency-associated tissue inflammation include: (i) to elucidate the cellular and molecular bases for the Th1 and Th17 hyperinflammation in CGD-related comorbidities and how the inflammation evolves to autoimmunity (ii) how subjects with low ROS production (e.g. gene carriers of CGD mutations) are affected by these pathogenic tissue inflammation, and (iii) developing therapies that restore NOX2 function in targeted immune cells, enhancing ROS-driven microbial killing while preventing oxidant stress-induced tissue damage, and addressing autoinflammation and autoimmune issues in CGD patients.