Rubicon promotes the M2 polarization of Kupffer cells via LC3-associated phagocytosis-mediated clearance to improve liver transplantation

Chen, Yajun; He, Ying; Wu, Xin-yi; Xu, Xuesong; Gong, Junhua; Chen, Yong; Gong, Jianping

doi:10.1016/j.cellimm.2022.104556

Cited by 10 publications

(9 citation statements)

References 41 publications

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“…In the same line, in a mouse liver transplantation model, the promotion of Kupffer cell clearance capacity from apoptotic T-cells resulted in a reduced rejection activity index. The improved liver graft function was associated with an M2 polarization of Kupffer cells triggered by PUFAs from degraded T-cells which in turn activates PPARγ [118].…”

Section: Tissue-resident Macrophages (Trm)mentioning

confidence: 97%

Multiple Shades of Gray—Macrophages in Acute Allograft Rejection

Lackner

Ebner

Watschinger

et al. 2023

IJMS

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Long-term results following solid organ transplantation do not mirror the excellent short-term results achieved in recent decades. It is therefore clear that current immunosuppressive maintenance protocols primarily addressing the adaptive immune system no longer meet the required clinical need. Identification of novel targets addressing this shortcoming is urgently needed. There is a growing interest in better understanding the role of the innate immune system in this context. In this review, we focus on macrophages, which are known to prominently infiltrate allografts and, during allograft rejection, to be involved in the surge of the adaptive immune response by expression of pro-inflammatory cytokines and direct cytotoxicity. However, this active participation is janus-faced and unspecific targeting of macrophages may not consider the different subtypes involved. Under this premise, we give an overview on macrophages, including their origins, plasticity, and important markers. We then briefly describe their role in acute allograft rejection, which ranges from sustaining injury to promoting tolerance, as well as the impact of maintenance immunosuppressants on macrophages. Finally, we discuss the observed immunosuppressive role of the vitamin-like compound tetrahydrobiopterin and the recent findings that suggest the innate immune system, particularly macrophages, as its target.

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Section: Tissue-resident Macrophages (Trm)mentioning

confidence: 97%

Multiple Shades of Gray—Macrophages in Acute Allograft Rejection

Lackner

Ebner

Watschinger

et al. 2023

IJMS

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“…Kupffer cell polarization is controlled through numerous cytokines and signals, raising an option for treatment to induce liver graft tolerance via inhibiting Kupffer polarization 161 . Studies prove that IL‐34, soluble fibrinogen‐like protein 2 (sFGL2), scavenger receptor class F member 1 (SCARF1), and Rubicon can stimulate M2 polarization of Kupffer cells and impede acute rejection of liver grafts in animal models 114–117 …”

Section: Tolerance and Efferocytosis Or How Apoptotic Cells Direct Im...mentioning

confidence: 99%

“…Polyunsaturated fatty acids, a byproduct of apoptotic T‐cell breakdown, have been demonstrated to activate peroxisome proliferator‐activated receptor‐gamma (PPARγ), inducing M2 polarization of Kupffer cells isolated from mouse liver tissue. Improved AC clearance in acute rejection is facilitated by Rubicon‐mediated LC3‐associated phagocytosis, which promotes M2 polarization of Kupffer cells and creates a microenvironment supportive of liver transplantation 117 …”

Section: Tolerance and Efferocytosis Or How Apoptotic Cells Direct Im...mentioning

confidence: 99%

“…[ 105,106] B-cells Mice Chronic failure of vascularized heart transplant emerges in just the existence of B-cells and the total lack of antibodies [107] Mice Improved tolerance transplantation [108][109][110] Mice Graft tolerance alters donor-specific B cell fortune to repress de novo alloreactive B-cells [111] Kupffer cells Rats Prohibition of Kupffer cell activity enhances adipose-derived stem cells graft into liver tissue [112] Rats XBP1s repression rescued rat liver transplants through JAK-STAT moderated Kupffer cells polarization [113] Rats Mice IL-34, sFGL2, SCARF1, and Rubicon can stimulate M2 polarization of Kupffer cells and impede acute rejection of liver grafts [114][115][116][117] Neutrophil cells Mouse skin graft model Neutrophil depletion delayed acute rejection by weakening the employment of allocative CD8 + T memory cells [118] 14 Kidney transplant recipients An important function of NETs in kidney acute antibody-mediated rejection [119] Mice Neutrophils release CSF1 stimulate macrophage polarization, and lead to facilitates graft tolerance [120] Abbreviations: CSF1, colony-stimulating factor 1; DCreg, regulatory DC; EBI3, Epstein-Barr Virus-Induced Gene 3; IFN-γ, interferon-gamma; Mreg, regulatory macrophage; NET, neutrophil extracellular trap; sFGL2, soluble fibrinogen-like protein 2; TGF-β, transforming growth factor-beta; Tol-DC, tolerogenic DC; XBP1, X-box binding protein 1.…”

Section: Macrophagesmentioning

confidence: 99%

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The role of efferocytosis and transplant rejection: Strategies in promoting transplantation tolerance using apoptotic cell therapy and/or synthetic particles

Vafadar,

Vosough,

Jahromi

et al. 2023

Cell Biochemistry & Function

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Recently, efforts have been made to recognize the precise reason(s) for transplant failure and the process of rejection utilizing the molecular signature. Most transplant recipients do not appreciate the unknown length of survival of allogeneic grafts with the existing standard of care. Two noteworthy immunological pathways occur during allogeneic transplant rejection. A nonspecific innate immune response predominates in the early stages of the immune reaction, and allogeneic antigens initiate a donor‐specific adaptive reaction. Though the adaptive response is the major cause of allograft rejection, earlier pro‐inflammatory responses that are part of the innate immune response are also regarded as significant in graft loss. The onset of the innate and adaptive immune response causes chronic and acute transplant rejection. Currently employed immunosuppressive medications have shown little or no influence on chronic rejection and, as a result, on overall long‐term transplant survival. Furthermore, long‐term pharmaceutical immunosuppression is associated with side effects, toxicity, and an increased risk of developing diseases, both infectious and metabolic. As a result, there is a need for the development of innovative donor‐specific immunosuppressive medications to regulate the allorecognition pathways that induce graft loss and to reduce the side effects of immunosuppression. Efferocytosis is an immunomodulatory mechanism with fast and efficient clearance of apoptotic cells (ACs). As such, AC therapy strategies have been suggested to limit transplant‐related sequelae. Efferocytosis‐based medicines/treatments can also decrease the use of immunosuppressive drugs and have no detrimental side effects. Thus, this review aims to investigate the impact of efferocytosis on transplant rejection/tolerance and identify approaches using AC clearance to increase transplant viability.

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“…Our study demonstrated that overexpression of Rubicon, significantly increased the proteins and ROS required for LC3-associated phagocytosis (LAP), as well as the recruitment of LC3II and the fusion of phagosomes with lysosomes. This effectively enhanced the scavenging ability of Kupffer cells on apoptotic T cells ( Chen et al, 2022 ). Overexpression of F1 scavenger receptor (SCARF1) in Figures 1 , 2 Kupffer cells enhances phagocytosis via the calcium-dependent PI3K-AKT-STAT3 signaling pathway, effectively reducing acute rejection after liver transplantation, increasing clearance of apoptotic cells, improving liver function and promoting immune tolerance post-transplantation ( Xu et al, 2021 ).…”

Section: The Role Of Different Functions Of Kupffer Cells In the Esta...mentioning

confidence: 99%

Role of Kupffer cells in tolerance induction after liver transplantation

Zheng

Yang

Jiang

et al. 2023

Front. Cell Dev. Biol.

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Currently, liver transplantation has reached a level of maturity where it is considered an effective treatment for end-stage liver disease and can significantly prolong the survival time of patients. However, acute and chronic rejection remain major obstacles to its efficacy. Although long-term use of immunosuppressants can prevent rejection, it is associated with serious side effects and significant economic burden for patients. Therefore, the investigation of induced immune tolerance holds crucial theoretical significance and socio-economic value. In fact, the establishment of immune tolerance in liver transplantation is intricately linked to the unique innate immune system of the liver. Kupffer cells, as a crucial component of this system, play a pivotal role in maintaining the delicate balance between inflammatory response and immune tolerance following liver transplantation. The important roles of different functions of Kupffer cells, such as phagocytosis, cell polarization, antigen presentation and cell membrane proteins, in the establishment of immune tolerance after transplantation is comprehensively summarized in this paper. Providing theoretical basis for further study and clinical application of Kupffer cells in liver transplantation.

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Rubicon promotes the M2 polarization of Kupffer cells via LC3-associated phagocytosis-mediated clearance to improve liver transplantation

Cited by 10 publications

References 41 publications

Multiple Shades of Gray—Macrophages in Acute Allograft Rejection

Multiple Shades of Gray—Macrophages in Acute Allograft Rejection

The role of efferocytosis and transplant rejection: Strategies in promoting transplantation tolerance using apoptotic cell therapy and/or synthetic particles

Role of Kupffer cells in tolerance induction after liver transplantation

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