# Cytochrome b5 reductase orchestrates IL-1β production in macrophages through FAD

## TL;DR

This study shows how a protein called CYB5R5 reduces inflammation in immune cells by controlling a key signaling pathway.

## Contribution

The novel finding is that CYB5R5 regulates IL-1β production in macrophages via FAD-LSD1 signaling and histone demethylation.

## Key findings

- CYB5R5 inhibits IL-1β production in M1 macrophages by enhancing FAD-LSD1 signaling.
- CYB5R5 lowers NLRP3 inflammasome assembly through demethylation of C1q-coding genes.
- Myeloid CYB5R5 depletion worsens LPS-induced sepsis in mice.

## Abstract

The cytochrome-b5 reductases (CYB5Rs) regulate cellular redox balance and contribute to the pathogenesis of inflammatory diseases. However, the roles of CYB5R5 in macrophages remain poorly understood and require further elucidation. In this study, we revealed that CYB5R5 orchestrates macrophage inflammation by inhibiting interleukin (IL)-1β production from M1 macrophages. Mechanistically, CYB5R5 enhances flavin adenine dinucleotide (FAD)-lysine demethylase1 (LSD1) signaling to regulate the histone demethylation of complement component 1, q subcomponent (C1q)-coding genes, thereby lowering NLRP3 inflammasome assembly. We also found that myeloid depletion of Cyb5r5 in mice exacerbates inflammatory responses in LPS-induced sepsis. This study reveals that CYB5R5 attenuates M1 macrophage polarization via metabolic and epigenetic reprogramming mechanism, thus providing potential therapeutic targets for macrophage-mediated inflammatory disorders.