Coinhibition of mTORC1/mTORC2 and RhoA /ROCK pathways prevents chronic rejection of rat cardiac allografts

Chen, Wei; Chen, Wenhao; Li, Xian Chang; Ghobrial, Rafik M.; Kloc, Małgorzata

doi:10.1016/j.tpr.2018.09.002

Cited by 3 publications

(3 citation statements)

References 33 publications

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“…This is not surprising in the light of the recent discovery that It must be noted here that Fingolimod, besides inhibiting the RhoA pathway, also inhibits the mTORC2. The mTORC2, in contrast to the mTORC1, which mainly controls cell proliferation, growth, and metabolism, co-regulates, together with the RhoA, actin polymerization [4,[73][74][75]. Thus, the effects of Fingolimod on th actin cytoskeleton may be a sum of RhoA and mTORC2 inhibition.…”

Section: Transplantation Model and Methods To Study Macrophagesmentioning

confidence: 99%

RhoA- and Actin-Dependent Functions of Macrophages from the Rodent Cardiac Transplantation Model Perspective -Timing Is the Essence

Kloc

Uosef

Villagran

et al. 2021

Biology

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The small GTPase RhoA, and its down-stream effector ROCK kinase, and the interacting Rac1 and mTORC2 pathways, are the principal regulators of the actin cytoskeleton and actin-related functions in all eukaryotic cells, including the immune cells. As such, they also regulate the phenotypes and functions of macrophages in the immune response and beyond. Here, we review the results of our and other’s studies on the role of the actin and RhoA pathway in shaping the macrophage functions in general and macrophage immune response during the development of chronic (long term) rejection of allografts in the rodent cardiac transplantation model. We focus on the importance of timing of the macrophage functions in chronic rejection and how the circadian rhythm may affect the anti-chronic rejection therapies.

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Section: Transplantation Model and Methods To Study Macrophagesmentioning

confidence: 99%

RhoA- and Actin-Dependent Functions of Macrophages from the Rodent Cardiac Transplantation Model Perspective -Timing Is the Essence

Kloc

Uosef

Villagran

et al. 2021

Biology

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“…It is known that M1 and M2 macrophages differ in shape; the M1 are round and M2 are elongated. It has been shown that cell elongation and migration depends on the translocation of mitochondria to the most energy‐demanding regions of the cell, where the actin cytoskeleton undergoes the most intense reorganisation (Boldogh & Pon, ; Cunniff, McKenzie, Heintz, & Howe, ; Schuler et al, ), and that a disruption of macrophage mitochondria and ATP/ADP homeostasis reverses M2 to the M1 phenotype (Chen, Chen, Li, Ghobrial, & Kloc, ). Mitochondria, besides producing energy, also produce the reactive oxygen species (ROS), which are the source of oxidative stress and bactericidal activities of M1 macrophages (Hall et al, ; Mills & O'Neill, ).…”

Section: Macrophage Mitochondria Respiration and Accelerated Wound mentioning

confidence: 99%

Macrophage functions in wound healing

Kloc

Ghobrial

Wosik

et al. 2018

J Tissue Eng Regen Med

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Macrophages play a crucial role in regeneration and consecutive phases of wound healing. In this review, we summarise current knowledge on the ontogeny, origin, phenotypical heterogeneity, and functional exchangeability of macrophages participating in these processes. We also describe the genetic, pharmacologic, and bioengineering methods for manipulation of macrophage phenotype and functions and their potential for development of the novel, clinically applicable therapies.

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“…This may possibly be due to mTORC2 inhibition resulting in a pro-inflammatory effect that would be consistent with mTORC2 deletion in DC promoting an inflammatory phenotype 24 or/and to limited bioavailability. Recently, Chen et al 54 reported that coinhibition of the mTORC1/2 (with everolimus) and RhoA/ROCK pathways in rat heart allograft recipients prevented chronic rejection. There is also evidence that the rapalogue everolimus is more effective than sirolimus at antagonizing both mTORC1 and mTORC2, the latter of which is critical in endothelial cell functional changes leading to transplant vasculopathy in human organ transplantation after HLA I crosslinking 55 .…”

Section: Pharmacologic Targeting Of Mtorc2 and Transplant Outcomementioning

confidence: 99%

The “other” mTOR complex: New insights into mTORC2 immunobiology and their implications

Dai

Thomson

2019

American Journal of Transplantation

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A central role of the mechanistic target of rapamycin (mTOR) in regulation of fundamental cell processes is well-recognized. mTOR functions in two distinct complexes: rapamycin-sensitive mTOR complex (C) 1 and rapamycin-insensitive mTORC2. While the role of mTORC1 in shaping immune responses, including transplant rejection, and the influence of its antagonism in promoting allograft tolerance have been studied extensively using rapamycin, lack of selective small molecule inhibitors has limited understanding of mTORC2 biology. Within the past few years, however, intracellular localization of mTORC2, its contribution to mitochondrial fitness, cell metabolism, cytoskeletal modeling and cell migration, and its role in differentiation and function of immune cells have been described. Studies in mTORC2 knockdown/knockout mouse models and a new class of dual mTORC1/2 inhibitors, have shed light on the immune regulatory functions of mTORC2. These include regulation of antigen-presenting cell, NK cell, T cell subset and B cell differentiation and function. mTORC2 has been implicated in regulation of ischemia/ reperfusion injury and graft rejection. Potential therapeutic benefits of antagonizing mTORC2 to inhibit chronic rejection have also been described, while selective in vivo targeting strategies using nanotechnology have been developed. We briefly review and discuss these developments and their implications.

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Coinhibition of mTORC1/mTORC2 and RhoA /ROCK pathways prevents chronic rejection of rat cardiac allografts

Cited by 3 publications

References 33 publications

RhoA- and Actin-Dependent Functions of Macrophages from the Rodent Cardiac Transplantation Model Perspective -Timing Is the Essence

RhoA- and Actin-Dependent Functions of Macrophages from the Rodent Cardiac Transplantation Model Perspective -Timing Is the Essence

Macrophage functions in wound healing

The “other” mTOR complex: New insights into mTORC2 immunobiology and their implications

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