Multicellular immune dynamics implicate PIM1 as a potential therapeutic target for uveitis

Li, He; Xie, Lihui; Zhu, Lei; Li, Zhaohuai; Wang, Rong; Liu, Xiuxing; Huang, Zhaofeng; Chen, Binyao; Gao, Yuehan; Wei, Lai; Ju, Rong; Liu, Yizhi; Liu, Xialin; Zheng, Yingfeng; Su, Wenru

doi:10.1038/s41467-022-33502-7

Cited by 20 publications

(25 citation statements)

References 71 publications

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“…Studies on Jun , Bst2 , and Klf6 have indicated the involvement of these molecules in a variety of tumors [ 48 – 51 ]. Pim1 has been reported to regulate the differentiation of T and B cells [ 52 , 53 ]. Pim1 also promotes Cxcr4 cell surface expression, thus regulating cell migration [ 54 ].…”

Section: Resultsmentioning

confidence: 99%

Beneficial mechanisms of dimethyl fumarate in autoimmune uveitis: insights from single-cell RNA sequencing

Zhu,

Li,

Peng

et al. 2024

J Neuroinflammation

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Background Dimethyl fumarate (DMF) is a fumaric acid ester that exhibits immunoregulatory and anti-inflammatory properties. However, the function of DMF in autoimmune uveitis (AU) is incompletely understood, and studies comprehensively exploring the impact of DMF on immune cells are still lacking. Methods To explore the function of DMF in uveitis and its underlying mechanisms, we conducted single-cell RNA sequencing (scRNA-seq) on the cervical draining lymph node (CDLN) cells of normal, experimental autoimmune uveitis (EAU), and DMF-treated EAU mice. Additionally, we integrated scRNA-seq data of the retina and CDLNs to identify the potential impact of DMF on ocular immune cell infiltration. Flow cytometry was conducted to verify the potential target molecules of DMF. Results Our study showed that DMF treatment effectively ameliorated EAU symptoms. The proportional and transcriptional alterations in each immune cell type during EAU were reversed by DMF treatment. Bioinformatics analysis in our study indicated that the enhanced expression of Pim1 and Cxcr4 in EAU was reversed by DMF treatment. Further experiments demonstrated that DMF restored the balance between effector T (Teff) /regulatory T (Treg) cells through inhibiting the pathway of PIM1-protein kinase B (AKT)-Forkhead box O1 (FOXO1). By incorporating the scRNA-seq data of the retina from EAU mice into analysis, our study identified that T cells highly expressing Pim1 and Cxcr4 were enriched in the retina. DMF repressed the ocular infiltration of Teff cells, and this effect might depend on its inhibition of PIM1 and CXCR4 expression. Additionally, our study indicated that DMF might reduce the proportion of plasma cells by inhibiting PIM1 expression in B cells. Conclusions DMF effectively attenuated EAU symptoms. During EAU, DMF reversed the Teff/Treg cell imbalance and suppressed the ocular infiltration of Teff cells by inhibiting PIM1 and CXCR4 expression. Thus, DMF may act as a new drug option for the treatment of AU.

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Section: Resultsmentioning

confidence: 99%

Beneficial mechanisms of dimethyl fumarate in autoimmune uveitis: insights from single-cell RNA sequencing

Zhu,

Li,

Peng

et al. 2024

J Neuroinflammation

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“…Patients with AU often suffer from persistent inflammation caused by autoimmune‐mediated damage to the targeted retinal and uveal tissues 3,4 . Utilizing multi‐omics approaches, accumulated studies have demonstrated immune disturbance in the eyes of AU cases 5–7 . However, the precise mechanism underlying dynamic alterations of the intraocular immune microenvironment in the initiation and progression of AU is still not fully elucidated.…”

Section: Introductionmentioning

confidence: 99%

Single‐cell RNA sequencing reveals inflammatory retinal microglia in experimental autoimmune uveitis

Liu,

Liao,

et al. 2024

MedComm

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Autoimmune uveitis (AU) is a kind of immune‐mediated disease resulting in irreversible ocular damage and even permanent vision loss. However, the precise mechanism underlying dynamic immune changes contributing to disease initiation and progression of AU remains unclear. Here, we induced an experimental AU (EAU) model with IRBP651‐670 and found that day[D]14 was the inflammatory summit with remarking clinical and histopathological manifestations and the activation of retinal microglia exhibited a time‐dependent pattern in the EAU course. We conducted single‐cell RNA sequencing of retinal immune cells in EAU mice at four time points and found microglia constituting the largest proportion, especially on D14. A novel inflammatory subtype (Cd74high Ccl5high) of retinal microglia was identified at the disease peak that was closely associated with modulating immune responses. In vitro experiments indicated that inflammatory stimuli induced proinflammatory microglia with the upregulation of CD74 and CCL5, and CD74 overexpression in microglia elicited their proinflammatory phenotype via nuclear factor‐kappa B signaling that could be attenuated by the treatment of neutralizing CCL5 antibody to a certain extent. In‐vivo blockade of Cd74 and Ccl5 effectively alleviated retinal microglial activation and disease phenotype of EAU. Therefore, we propose targeting CD74 and CCL5 of retinal microglia as promising strategies for AU treatment.

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“…It has also been shown recently that Pim1/Pim2 deficiency prevented mTORc1 activation and the proliferation of nonconventional intra-epithelial gut CD8 T lymphocytes (IEL) in response to the cytokine IL-15 (James et al, 2021). Elevated PIM kinase expression has been noted in patient T cells for a number of autoimmune conditions, including rheumatoid arthritis, uveitis and coeliac disease, and PIM kinase inhibition has been proposed as a possible intervention to dampen autoimmunity (James et al, 2021;Maney et al, 2021;Li et al, 2022). PIM kinase inhibitors have also entered clinical trials to treat some cancers and there is active interest in combining these with immunotherapies (Clements and Warfel, 2022).…”

Section: Introductionmentioning

confidence: 99%

PIM kinase control of CD8 T cell protein synthesis and cell trafficking

Marchingo,

Spinelli,

Pathak

et al. 2024

Preprint

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Integration of a large network of kinase signalling pathways co-ordinates changes in the transcription, translation and metabolic events required for T cell activation and differentiation. The present study explores the role of the Serine/Threonine kinases PIM1 and PIM2 in controlling murine CD8 T lymphocyte antigen receptor-mediated activation and differentiation in response to the cytokines Interleukin 2 (IL-2) or IL-15. We show that PIM kinases are dispensable for the differentiation programs controlled by the antigen-receptor and IL-15. There is however a selective role for the PIM kinases in the context of IL-2 regulation of CD8 T cell fate. One key insight was that the PIM kinases controlled the migratory capabilities of effector CD8 T cells, with Pim1/Pim2-deficient CD8 T cells unable to fully switch off the naive T cell chemokine and adhesion receptor program during effector differentiation. PIM kinases were also needed for IL-2 to sustain high expression of the glucose transporters SLC2A1 and SLC2A3 and to maintain activity of the nutrient sensing kinase mTORc1. Strikingly, PIM kinases did not have a dominant impact on IL-2-driven transcriptional programs but rather selectively modulated protein synthesis to shape cytotoxic T cell proteomes. This study reveals a selective role of PIM kinases in IL-2 control of CD8 T cells and highlights how regulated changes in protein synthesis can impact T cell phenotypes.

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Multicellular immune dynamics implicate PIM1 as a potential therapeutic target for uveitis

Cited by 20 publications

References 71 publications

Beneficial mechanisms of dimethyl fumarate in autoimmune uveitis: insights from single-cell RNA sequencing

Beneficial mechanisms of dimethyl fumarate in autoimmune uveitis: insights from single-cell RNA sequencing

Single‐cell RNA sequencing reveals inflammatory retinal microglia in experimental autoimmune uveitis

PIM kinase control of CD8 T cell protein synthesis and cell trafficking

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