# DOCK2 as a novel CD11c ligand in neutrophils to regulate reactive oxygen species production

## TL;DR

The paper discovers that CD11c interacts with DOCK2 in neutrophils to regulate the production of reactive oxygen species, revealing a new role for CD11c beyond traditional functions.

## Contribution

The study identifies DOCK2 as a novel CD11c ligand in neutrophils, linking CD11c to ROS production via Rac activation.

## Key findings

- CD11c-deficient neutrophils show impaired ROS generation but normal phagocytosis.
- Phosphoproteomic analysis reveals reduced DOCK2 phosphorylation in CD11c-deficient cells.
- CD11c directly interacts with DOCK2, promoting Rac activation and NADPH oxidase function.

## Abstract

CD11c (integrin αX) is one of the β2 integrin members traditionally recognized as a dendritic cell marker. It forms the CD11c/CD18 heterodimer—also known as complement receptor 4 (CR4)—and mediates ligand binding to complement fragments, fibrinogen, and intercellular adhesion molecules in vitro. Although its expression on dendritic cells and a subset of macrophage populations has been well recognized historically, recent findings reveal that it demonstrates a broader expression profile, including in neutrophils. In neutrophils, CD11c is predominantly intracellular, suggesting a non-canonical role beyond cellular adhesion. We previously identified IQGAP1 as an intracellular binding partner of CD11c/CD18, implicating this interaction in neutrophil maturation. Here, mature CD11c-deficient neutrophils displayed impaired reactive oxygen species (ROS) generation while maintaining normal phagocytosis, indicating a selective defect in oxidative burst. Given the central role of NADPH oxidase and Rac activation in ROS production, we hypothesized that CD11c would influence this pathway. Phosphoproteomic profiling revealed reduced phosphorylation of the Rac guanine nucleotide exchange factor DOCK2 in CD11c-deficient neutrophils upon phorbol 12-myristate 13-acetate (PMA) stimulation. The analysis involving immunoprecipitation and proteomics confirmed a CD11c–DOCK2 association. These results supported a model in which CD11c would directly engage DOCK2 to promote Rac activation and NADPH oxidase function, uncovering a novel integrin-mediated mechanism regulating neutrophil effector activity. This work expands the functional repertoire of CD11c and provides a new insight into integrin signaling in innate immunity.