Role of ELP3 in macrophage polarization

Macrophages are critical in anti-microbial and inflammatory activity in host defense as well as in the resolution of inflammation and wound healing. Their response to microenvironmental cues allows them to acquire distinct effector states in order to carry out multiple functions. Their plasticity helps macrophages to acquire tailored activities within tissues and is often addressed through the concept of macrophage polarization. Interferon-gamma is the canonical type 1 cytokine which, together with bacterial lipopolysaccharide (LPS) is associated with a type 1 immune environment and triggers a proinflammatory profile that is referred to as “M1” or “classical” macrophage polarization. In contrast, IL-4 and IL-13, which are cytokines typically associated with type 2 immune responses, trigger different responses in macrophages, resulting in what is often referred to as M2 macrophage polarization. M2 macrophages downplay inflammation, promote tissue repair and remodeling through the secretion of anti-inflammatory cytokines (IL-10), scavenging receptors and a variety of remodeling factors. Processes linked to M2 macrophage are involved in tumor growth and metastasis, in the cellular response to helminth infections as well as in insulin sensitivity in adipocytes.

Alain Chariot (WELBIO – ULiège) and his team report that translational reprogramming linked to macrophage polarization relies on Elp3, a tRNA-modifying enzyme involved in mRNA translation of mostly unknown candidates. Elp3 deficiency enhances M1 polarization, which potentiates inflammation in a mouse model of experimental colitis. On the other hand, Elp3 deficiency blocks M2 polarization in vivo, which delays Wnt-driven tumor initiation in the intestine. Mechanistically, Elp3 promotes mRNA translation of multiples candidates, including Ric8b, a mTORC2 activator. Elp3 also promotes the synthesis of several mitochondrial proteins, with important consequences in metabolic reprogramming linked to macrophage polarization. Therefore, these results highlight the key role of some tRNA modifications in the biology of immune cells.

Reference : Chen et al (2022) EMBO J, e109353

Source & photo : Alain Chariot