Itaconate as the endogenous brake of proinflammatory macrophage activation alleviates inflammation in liver fibrogenesis

Liver inflammation and fibrosis are reparative responses to chronic liver injury. Bone marrow-derived monocyte/macrophages (BMDMs) are key participants. Our previous study demonstrated that BMDM can be activated as a proinflammatory phenotype by sphingosine-1-phosphate (S1P). Aconitate decarboxylase 1 (ACOD1)/itaconate is an anti-inflammatory molecule. However, it remains unclear whether ACOD1/itaconate is involved in S1P-induced BMDM activation.

A methionine-choline-deficient and high-fat diet was used to induce liver injury and fibrosis in mice. To clarify the role of endogenous ACOD1/itaconate in BMDMs in liver fibrosis, we established 2 types of chimeric mice: (1) bone marrow (BM) Acod1 deficiency (WT or Acod1 knockout BM was transplanted into wild-type mice) and (2) exclusive BM Acod1 expression (WT or Acod1 knockout BM was transplanted into Acod1 knockout mice).

Single-cell RNA sequencing data revealed that Acod1 was highly expressed in injured BMDMs. Acod1+ BMDMs exhibited a proinflammatory phenotype with elevated expression of proinflammatory genes. In vitro, ACOD1 expression and itaconate production were upregulated in S1P-treated BMDMs. Endogenous ACOD1/itaconate in BMDMs suppressed BMDM proinflammatory activation by forming negative feedback with NF-κB signaling. S1P-regulated ACOD1 expression and BMDM activation via the same signaling pathway (S1PR2/MAPK/NF-κB signaling), indicating the endogenous brake function of ACOD1/itaconate. In chimeric mice with BM Acod1 deficiency, the abolition of the endogenous brake function of ACOD1/itaconate aggravated liver inflammation/fibrosis. Exclusive BM Acod1 expression showed the opposite effects.

ACOD1/itaconate exerts an endogenous brake function in the proinflammatory activation of BMDMs during chronic liver injury. Our data demonstrate the role of ACOD1/itaconate in S1P-induced BMDM activation, further indicating that ACOD1/itaconate is a potential therapeutic strategy for liver inflammation/fibrosis.