AUTHOR=Song Zhimin , Yoo Dae-Goon , Idol Rachel A. , Barbu Emilia Alina , Jacob Chaim O. , Dinauer Mary C. 

TITLE=Lupus-associated NCF2 variant p.R395W in the NADPH oxidase 2 complex results in a reduced production of reactive oxygen species by myeloid cells

JOURNAL=Frontiers in Lupus

VOLUME=Volume 1 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/lupus/articles/10.3389/flupu.2023.1186641

DOI=10.3389/flupu.2023.1186641

ISSN=2813-6934

ABSTRACT=The leukocyte NADPH oxidase 2 (NOX2) generates superoxide, and derivative reactive oxygen species play important roles in both host defense and immunoregulation. The rs13306575 genetic variant, resulting in an Arginine395→Tryptophan (R395W) substitution in the NOX2 NCF2 subunit, is associated with an increased risk of lupus in patients of Hispanic-American or of Korean ancestry.  Arginine395 resides within the NCF2 PB1 domain, and participates in a constitutive high-affinity interaction with the NOX2 NCF4 subunit to stabilize their expression.  However, whether this variant impacts NCF2 function and NOX2 activity is unknown.  To answer this question, mice expressing NCF2-R395W were generated using CRISPR/Cas9.  NCF2 and NCF4 expression were reduced by 2-fold in neutrophils, macrophages and dendritic cells homozygous for NCF2-R395W. Moreover, following stimulation with soluble or particulate stimuli, ROS production at the plasma membrane and within cells was reduced in all three myeloid lineages expressing NCF2-R395W.  Additional studies on Ncf2+/- mice, which have reduced expression of wild-type NCF2 but not NCF4, suggest that the reduced expression of both NCF2 and NCF4 contributes to the diminished NOX2 activity in NCF2-R395 mice.  These results establish that the lupus-associated rs13306575 p.R395W allele is a functional hypomorph.  The findings add to growing evidence implicating deficient NOX2 activity in the pathogenesis of lupus.