Itaconate-producing neutrophils regulate local and systemic inflammation following trauma

Abstract

Modulation of the immune response to initiate and halt the inflammatory process occurs both at the site of injury as well as systemically. Due to the evolving role of cellular metabolism in regulating cell fate and function, tendon injuries that undergo normal and aberrant repair were evaluated by metabolic profiling to determine its impact on healing outcomes. Metabolomics revealed an increasing abundance of the immunomodulatory metabolite itaconate within the injury site. Subsequent single-cell RNA-Seq and molecular and metabolomic validation identified a highly mature neutrophil subtype, not macrophages, as the primary producers of itaconate following trauma. These mature itaconate-producing neutrophils were highly inflammatory, producing cytokines that promote local injury fibrosis before cycling back to the bone marrow. In the bone marrow, itaconate was shown to alter hematopoiesis, skewing progenitor cells down myeloid lineages, thereby regulating systemic inflammation. Therapeutically, exogenous itaconate was found to reduce injury-site inflammation, promoting tenogenic differentiation and impairing aberrant vascularization with disease-ameliorating effects. These results present an intriguing role for cycling neutrophils as a sensor of inflammation induced by injury — potentially regulating immune cell production in the bone marrow through delivery of endogenously produced itaconate — and demonstrate a therapeutic potential for exogenous itaconate following tendon injury

Control of immune cell signaling by the immuno-metabolite itaconate

“…In a model of traumatic tendon injury, itaconate production was shown to promote neutrophilia by increasing granulocyte-monocyte progenitor (GMP) output from the bone marrow ( 79 ). Interestingly, neutrophils present at the injury site were the major producers of itaconate.…”

“…Interestingly, neutrophils present at the injury site were the major producers of itaconate. Still, exogenous administration of itaconate reduced inflammation and promoted resolution of inflammation, suggesting that also in neutrophils itaconate production may act as molecular brake to prevent exaggerated inflammation ( 79 ). An inhibitory effect of 4-OI on neutrophil formation of extracellular traps (NETs) has recently been described by Burczyk et al., associated with inhibition of HIF1α ( 80 ).…”

Multifaceted mitochondria in innate immunity

“…Furthermore, myeloid-derived IRG1 dampens neutrophil-mediated lung inflammation following M. tuberculosis infection, underscoring the importance of itaconate in vivo 189 . However, following trauma, itaconate-producing neutrophils play an important role in tissue inflammation and the wound healing process following tendon injury 190 . In contrast, itaconate production in DCs impairs anti-parasitic immune responses by promoting mtDNA-dependent PD-L1 expression following Plasmodium chabaudi infection, which limits CD8 + T cells 191 .…”