Independent and inter-dependent immunoregulatory effects of NCF1 and NOS2 in experimental autoimmune encephalomyelitis

Abstract

Background: Increasing evidence has suggested that a single nucleotide polymorphism in the Ncf1 gene is associated with experimental autoimmune encephalomyelitis (EAE). However, the mechanisms of NCF1-induced immunoregulatory effects remain poorly understood. In this study, we focus on NCF1 deficiency-mediated effects on EAE in NOS2 dependent and independent ways. Methods: To determine the effects of NCF1 and NOS2 during EAE development, we have established recombinant mouse strains deficient at NCF1 and/or NOS2 in a crossbreeding system. Different strains allow us to examine the entire course of the disease in the Nos2-null mice bearing a Ncf1 gene that encodes a mutated NCF1, deficient in triggering oxidative burst, after immunization with recombinant myelin oligodendrocyte glycoprotein (MOG) 79-96 peptides. The peptide-induced innate and adaptive immune responses were analyzed by flow cytometry.Results: NCF1-deficient mice developed a reduced susceptibility to EAE, whereas NCF1-NOS2 double-deficient mice developed an enhanced EAE, as compared with NOS2-deficient mice. Flow cytometry analyses show that double deficiencies resulted in an increase of neutrophils in the spleen, accompanied with higher release of interleukin-1β in neutrophils prior to EAE onset. The additional deficiency in NCF1 had no added effect on either interleukin-17 or interferon-γ secretion of T cells during the priming phase.Conclusions: These studies show that NCF1 and NOS2 interact to regulate peptide-induced EAE.

Neutrophil-derived reactive oxygen species promote tumor colonization

“…Previously, we and others have found a role of ROS in the regulation of IL-1β expression 12 , 23 . In this study, we show that ROS-sufficient neutrophils express an enhanced IL-1β in conditional knock-in mice (Fig.…”

“…It should be pointed out that the small compound histamine dihydrochloride might not specifically affect NK cells, and there is also genetic difference between the knockout mouse strains and naturally mutant strains. For an example, both Nox2 -knockout mice and Ncf1 -knockout mice have been reported to be protected from experimental autoimmune encephalomyelitis 44 , but the Ncf1 mutant mice exhibited an enhanced autoimmune encephalomyelitis 12 , 45 . Therefore, we further studied the role of NK cells in the Ncf1 mutant mice using anti-NK1.1 antibody 26 .…”

“…CD68-expressing cells, predominantly macrophages, are a critical mediator regarding autoimmune disease susceptibility, exhibiting the properties of both innate and adaptive immune responses. The downstream effect of the Ncf1 mutation includes regulation of T cells in autoimmune arthritis 10 , 11 and encephalomyelitis 12 , exaggerated type I interferon signaling in lupus autoimmunity 13 , 14 , innate interleukin 17 (IL-17) induction in psoriatic diseases 15 – 17 , and impairment of the capacity to form neutrophil extracellular traps in patients with gout 18 and gallstones 19 .…”

Natural Loss-of-Function Mutations in Qa2 and NCF1 Cause the Spread of Mannan-Induced Psoriasis

“…Using the susceptible Qa2 nul mice of B6R strain, we found that the Ncf1 mutation led to both ear and nail psoriasis. These results suggest that the Ncf1 mutation has an essential role in psoriasis spread, of which downstream pathways could be elicted by proinflammatory Ly6C monocytes to activate the local γδ T cells (Zhong et al 2020a;Zhong et al 2018b).…”

Noninvasive imaging of the lung NETosis by anti-Ly6G iron oxide nanoparticles

“…We have previously found that a natural mutation in the Ncf1 gene impairs the formation of the NADPH oxidase 2 (NOX2) complex and the generation of reactive oxygen species (ROS) [ 1 , 12 ], promotes the proliferation of autoreactive CD4 T cells in spontaneous arthritis [ 13 , 14 ], enhances autoimmune encephalomyelitis in the absence of inducible nitric oxide [ 15 ], promotes the spread of psoriasis through innate production of interleukin 17 (IL-17) [ 16 , 17 , 18 ], activates STAT1 signaling in exaggerated lupus [ 19 ], and suppresses NETosis in neutrophils prepared from patients with the chronic granulomatous disease and autoimmune disorders [ 3 , 20 ]. 147-base pair of NET DNA is typically packed around a histone octamer composed of two copies of each of the histones H3, H4, H2A, and H2B [ 21 ].…”