Abstract

Functional consequences for most inflammatory disease-associated loci are incompletely defined, including in the LACC1 (C13orf31) region. Here we show that human peripheral and intestinal myeloid-derived cells express laccase domain-containing 1 (LACC1); LACC1 is expressed in both the cytoplasm and mitochondria. Upon NOD2 stimulation of human macrophages, LACC1 associates with the NOD2-signalling complex, and is critical for optimal NOD2-induced signalling, mitochondrial ROS (mtROS) production, cytokine secretion and bacterial clearance. LACC1 constitutively associates with succinate dehydrogenase (SDH) subunit A, and amplifies pattern recognition receptor (PRR)-induced SDH activity, an important contributor to mtROS production. Relative to LACC1 Ile254, cells transfected with Crohn’s disease-risk LACC1 Val254 or LACC1 with mutations of the nearby histidines (249,250) have reduced PRR-induced outcomes. Relative to LACC1 Ile254 carriers, Val254 disease-risk carrier macrophages demonstrate decreased PRR-induced mtROS, signalling, cytokine secretion and bacterial clearance. Therefore, LACC1 is critical for amplifying PRR-induced outcomes, an effect that is attenuated by the LACC1 disease-risk variant.

Highlights

  • Functional consequences for most inflammatory disease-associated loci are incompletely defined, including in the laccase domain-containing 1 (LACC1) (C13orf31) region

  • We identify that LACC1 is expressed in both peripheral and intestinal human myeloid-derived cells and is required for optimal pattern recognition receptor (PRR)-induced mitochondrial reactive oxygen species (ROS) and ROS production, MAPK and NFkB pathway activation, cytokine secretion and intracellular bacterial clearance in primary human monocyte-derived macrophages (MDMs)

  • Given the importance of regulating PRR-initiated outcomes in intestinal immune homeostasis and the dysregulation in PRR pathway outcomes that can be observed in IBD1, we questioned whether the rs3764147 genotype in human LACC1 modulates PRR-initiated outcomes in human MDMs

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Summary

Introduction

Functional consequences for most inflammatory disease-associated loci are incompletely defined, including in the LACC1 (C13orf31) region. Relative to LACC1 Ile[254] carriers, Val[254] disease-risk carrier macrophages demonstrate decreased PRR-induced mtROS, signalling, cytokine secretion and bacterial clearance. An important role for host– microbial interactions is further highlighted by Crohn’s disease (CD)-associated loss-of-function polymorphisms in NOD2 (refs 1,2; encoding NOD2, a PRR that recognizes bacterial peptidoglycan) as well as in additional pathways regulating microbial clearance mechanisms, such as autophagy[3] and NADPH complex-mediated generation of reactive oxygen species (ROS)[4,5]. We identify that LACC1 is expressed in both peripheral and intestinal human myeloid-derived cells and is required for optimal PRR-induced mitochondrial ROS (mtROS) and ROS production, MAPK and NFkB pathway activation, cytokine secretion and intracellular bacterial clearance in primary human monocyte-derived macrophages (MDMs). We identify roles for human LACC1, and establish loss-of-function consequences for the LACC1 Val[254] IBD risk variant, thereby resulting in decreased amplification of PRR-induced mtROS, signalling, cytokines and bacterial clearance

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