Itaconate inhibits SYK through alkylation and suppresses inflammation against hvKP induced intestinal dysbiosis

Li, Yangguang; Xu, Yu; Li, Weizhen; Li, Jiayang; Wu, Wenqi; Kang, Jiaqi; Jiang, Haiyang; Liu, Peizhao; Liu, Juanhan; Gong, Wenbin; Li, Xuanheng; Ni, Chujun; Liu, Mingda; Chen, Lijuan; Li, Sicheng; Wu, Xiuwen; Zhao, Yun; Ren, Jianan

doi:10.1007/s00018-023-04971-w

Cited by 5 publications

(5 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…During microbial invasion, itaconate effectively restricts the growth of Pseudomonas indigofera by inhibiting isocitrate lyase activity, and its metabolite, itaconyl-CoA, also inhibits pathogen growth after Mycobacterium tuberculosis infection by regulating methylmalonyl-CoA mutase [ 42 , 43 ]. Moreover, itaconate potently restores the integrity of the intestinal barrier and alleviates dysbiosis of the gut microbiota in a model of hypervirulent Klebsiella pneumoniae infection [ 44 ]. Supplementation with dimethyl itaconate improves microbiome alterations and attenuates high-fat diet-mediated cognitive decline in mice [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Itaconate alleviates anesthesia/surgery-induced cognitive impairment by activating a Nrf2-dependent anti-neuroinflammation and neurogenesis via gut-brain axis

Kong,

Lyu,

Lin

et al. 2024

J Neuroinflammation

View full text Add to dashboard Cite

Background Postoperative cognitive dysfunction (POCD) is a common neurological complication of anesthesia and surgery in aging individuals. Neuroinflammation has been identified as a hallmark of POCD. However, safe and effective treatments of POCD are still lacking. Itaconate is an immunoregulatory metabolite derived from the tricarboxylic acid cycle that exerts anti-inflammatory effects by activating the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. In this study, we investigated the effects and underlying mechanism of 4-octyl itaconate (OI), a cell-permeable itaconate derivative, on POCD in aged mice. Methods A POCD animal model was established by performing aseptic laparotomy in 18-month-old male C57BL/6 mice under isoflurane anesthesia while maintaining spontaneous ventilation. OI was intraperitoneally injected into the mice after surgery. Primary microglia and neurons were isolated and treated to lipopolysaccharide (LPS), isoflurane, and OI. Cognitive function, neuroinflammatory responses, as well as levels of gut microbiota and their metabolites were evaluated. To determine the mechanisms underlying the therapeutic effects of OI in POCD, ML385, an antagonist of Nrf2, was administered intraperitoneally. Cognitive function, neuroinflammatory responses, endogenous neurogenesis, neuronal apoptosis, and Nrf2/extracellular signal-related kinases (ERK) signaling pathway were evaluated. Results Our findings revealed that OI treatment significantly alleviated anesthesia/surgery-induced cognitive impairment, concomitant with reduced levels of the neuroinflammatory cytokines IL-1β and IL-6, as well as suppressed activation of microglia and astrocytes in the hippocampus. Similarly, OI treatment inhibited the expression of IL-1β and IL-6 in LPS and isoflurane-induced primary microglia in vitro. Intraperitoneal administration of OI led to alterations in the gut microbiota and promoted the production of microbiota-derived metabolites associated with neurogenesis. We further confirmed that OI promoted endogenous neurogenesis and inhibited neuronal apoptosis in the hippocampal dentate gyrus of aged mice. Mechanistically, we observed a decrease in Nrf2 expression in hippocampal neurons both in vitro and in vivo, which was reversed by OI treatment. We found that Nrf2 was required for OI treatment to inhibit neuroinflammation in POCD. The enhanced POCD recovery and promotion of neurogenesis triggered by OI exposure were, at least partially, mediated by the activation of the Nrf2/ERK signaling pathway. Conclusions Our findings demonstrate that OI can attenuate anesthesia/surgery-induced cognitive impairment by stabilizing the gut microbiota and activating Nrf2 signaling to restrict neuroinflammation and promote neurogenesis. Boosting endogenous itaconate or supplementation with exogenous itaconate derivatives may represent novel strategies for the treatment of POCD.

show abstract

Section: Discussionmentioning

confidence: 99%

Itaconate alleviates anesthesia/surgery-induced cognitive impairment by activating a Nrf2-dependent anti-neuroinflammation and neurogenesis via gut-brain axis

Kong,

Lyu,

Lin

et al. 2024

J Neuroinflammation

View full text Add to dashboard Cite

show abstract

“…Cellular compartments are indicated where modification or inhibition of target proteins occurs. CLR (C-type lectin receptors) and FcγR (Fc gamma receptors) are shown as SYK-coupled receptors putatively affected by itaconation of SYK ( 46 ); cytokine receptors in addition to IL-4 receptor and IFNAR may be affected by itaconate ( 47 ), given the pleiotropic function of JAK1.…”

Section: Impact Of Itaconate On Cell Signaling and Metabolismmentioning

confidence: 99%

“…SYK was found to be itaconated at cysteines 587 and 591 (mouse), corresponding to Cys593 and Cys597 in human SYK, which are located in the kinase domain. Mutation of Cys593 in human SYK abrogated inhibition by itaconate and its derivatives ( 46 ). Administration of itaconate or 4-OI to mice infected with hvKP reduced inflammation in the gut, weight loss and mortality, whereas Acod1 -/- mice showed a more severe phenotype ( 46 ).…”

Section: Impact Of Itaconate On Cell Signaling and Metabolismmentioning

confidence: 99%

“…Mutation of Cys593 in human SYK abrogated inhibition by itaconate and its derivatives ( 46 ). Administration of itaconate or 4-OI to mice infected with hvKP reduced inflammation in the gut, weight loss and mortality, whereas Acod1 -/- mice showed a more severe phenotype ( 46 ). It will be interesting to see whether other, well characterized SYK-activating receptors in innate immune cells, e.g.…”

Section: Impact Of Itaconate On Cell Signaling and Metabolismmentioning

confidence: 99%

“…SYK plays an essential role in the signaling of the B cell receptor, activating Fc receptors and myeloid C-type lectin receptors like Dectin-1 and Mincle (65). In a mouse model of infection with hypervirulent Klebsiella pneumoniae (hvKP), Li et al observed strong SYK activation in macrophages that was coupled to expression of ACOD1 and production of itaconate (46). Exogenous itaconate, 4-OI or DMI reduced cytokine production and SYK activation in macrophages exposed to hvKP, whereas enhanced phosphorylation of SYK occurred in Acod1 -/macrophages.…”

Section: Sykmentioning

confidence: 99%

See 2 more Smart Citations

Control of immune cell signaling by the immuno-metabolite itaconate

Lang,

Siddique

2024

Front. Immunol.

View full text Add to dashboard Cite

Immune cell activation triggers signaling cascades leading to transcriptional reprogramming, but also strongly impacts on the cell’s metabolic activity to provide energy and biomolecules for inflammatory and proliferative responses. Macrophages activated by microbial pathogen-associated molecular patterns and cytokines upregulate expression of the enzyme ACOD1 that generates the immune-metabolite itaconate by decarboxylation of the TCA cycle metabolite cis-aconitate. Itaconate has anti-microbial as well as immunomodulatory activities, which makes it attractive as endogenous effector metabolite fighting infection and restraining inflammation. Here, we first summarize the pathways and stimuli inducing ACOD1 expression in macrophages. The focus of the review then lies on the mechanisms by which itaconate, and its synthetic derivatives and endogenous isomers, modulate immune cell signaling and metabolic pathways. Multiple targets have been revealed, from inhibition of enzymes to the post-translational modification of many proteins at cysteine or lysine residues. The modulation of signaling proteins like STING, SYK, JAK1, RIPK3 and KEAP1, transcription regulators (e.g. Tet2, TFEB) and inflammasome components (NLRP3, GSDMD) provides a biochemical basis for the immune-regulatory effects of the ACOD1-itaconate pathway. While the field has intensely studied control of macrophages by itaconate in infection and inflammation models, neutrophils have now entered the scene as producers and cellular targets of itaconate. Furthermore, regulation of adaptive immune responses by endogenous itaconate, as well as by exogenously added itaconate and derivatives, can be mediated by direct and indirect effects on T cells and antigen-presenting cells, respectively. Taken together, research in ACOD1-itaconate to date has revealed its relevance in diverse immune cell signaling pathways, which now provides opportunities for potential therapeutic or preventive manipulation of host defense and inflammation.

show abstract

The anti-inflammatory effects of itaconate and its derivatives in neurological disorders

Kong,

Xu,

Mou

et al. 2024

Cytokine & Growth Factor Reviews

View full text Add to dashboard Cite

Itaconate inhibits SYK through alkylation and suppresses inflammation against hvKP induced intestinal dysbiosis

Cited by 5 publications

References 54 publications

Itaconate alleviates anesthesia/surgery-induced cognitive impairment by activating a Nrf2-dependent anti-neuroinflammation and neurogenesis via gut-brain axis

Itaconate alleviates anesthesia/surgery-induced cognitive impairment by activating a Nrf2-dependent anti-neuroinflammation and neurogenesis via gut-brain axis

Control of immune cell signaling by the immuno-metabolite itaconate

The anti-inflammatory effects of itaconate and its derivatives in neurological disorders

Contact Info

Product

Resources

About