Targeting AMPK and mTOR pathways in Eczema

Targeting AMPK and mTOR pathways in Eczema  

Rationale

Eczema or atopic dermatitis is chronic inflammation of the skin characterized by numerous relapses. Eczematous patches, plaques, epidermal edema along with immunological cells in the infiltrate are the histologic features of eczema. It has been shown recently that CD4 and CD8 T-cells and the inflammatory cytokines such as IFN-γ, TNF-α, play a dominant role in the pathology of atopic dermatitis. Recent literature also suggests using biologics targeted to counter these pro-inflammatory cytokines. However, recently more focus has been put towards understanding the metabolic pathways of T-cell activation. Particular focus has been put in understanding the fatty acid metabolism involved in the T-cells.  It has been shown that T-cell activation leads to increased glucose uptake and activation of PI3K/AKT and mTOR pathway. Utilization of fatty acids for energy needs, i.e. using beta oxidation on the other hand leads to the development of different lineage of T-cells such as CD4 regulatory T-cells (Tregs) which are a class of suppressive T-cells. AMP activated protein kinase (AMPK) is master regulator of metabolic pathways. AMPK is activated especially during the cell starvation and reduced ATP levels. AMPK has also been shown to be activated during decreased glucose levels in the cells and thus shown to enhance the fatty acid beta oxidation pathway. It therefore comes as no surprise that AMPK pathway activation has been shown to counter mTOR pathway activation and its negative regulation. More interestingly, mTOR pathway deregulation and activation has also been demonstrated in psoriatic plaques suggesting that mTOR pathway activation may not only be involved in T-cell compartment but also in the eczematous skin microenvironment. Interestingly AMPK pathway has also been shown to inhibit the inflammatory NF-κB pathway in the tumor microenvironment, suggesting AMPK activation will work towards inhibiting T-cells, inflammation, and mTOR pathway activation in the eczematous skin microenvironment. It is therefore a valid option to activate AMPK pathway and block mTOR pathway, in combination to treat eczema or atopic dermatitis.

Background and Significance

            Eczema has been described as a chronic inflammatory condition of skin coupled with pruritis (1). The condition has been shown frequently to be associated with Th2 T-cell response to common environmental antigens. It has also been proposed that compromised barrier function of skin contributes towards the pathology of the disease. Although the compromised barrier has been suggested to promote the penetration of environmental allergens or microorganisms, other factors such as innate and adaptive immune responses have been put forward as necessary for the development and progression of the disease (2).

Role of T-cells in eczema

Further examination of role of T-cells and cytokines suggest a Th2 polarization with contribution from IL-4, leading to class-switching of antibodies towards IgE phenotype. Keratinocytes have also been shown to present MHC class I and II molecules on their surface and present antigens to CD8 and CD4 T-cells respectively (3). This has been shown leading to keratinocytes apoptosis further contributing to spongiosis which is another characteristic of eczema. Keratinocytes are thus believed to be the targets of T-cells, contributing towards disruption of skin barrier leading to eczema (1). Several broad T-cells targeting therapeutics such as cyclosporine, efalizumab have shown promise, suggesting role of T-cells in the pathology of eczema (4).

            Apart from the role of Th2 type T-cells and cytokines, Treg cells disorders have also been shown towards the development of chronic inflammatory phenotypes. IPEX syndrome which leads to immune dysregulation, polyendocrinopathy and enteropathy was found to be due to mutations in Foxp3, which is the master transcription factor necessary for the function of Tregs (5-7). Scurfy mutant mice which have disruption of Foxp3 develop spontaneous skin inflammation due to dysregulated T-cells (8). All this and other data do suggest that lack of Treg regulation of T-cells may contribute towards the pathology of atopic dermatitis and one way to treat the disease would be to reestablish this regulation.

AMPK/mTOR pathway      

Perturbations in AMP/ATP ratio is in the center of cellular metabolism, and is tightly regulated (9). An energy rich state means increased ATP levels and energy low state would mean increased AMP levels. AMPK is an energy sensor that shuts down energy consumption and enhances energy production trying to restore ATP levels to reduce the AMP/ATP ratio (10). AMPK has been shown to be activated during metabolic stress where there is an increase in AMP/ATP ratio. In addition, recent studies have shown that ROS is another upstream activator of AMPK (11,12). MTOR is another important regulator of cellular metabolism, cellular growth and proliferation (13). In normal cells, AMPK and mTOR act inversely where AMPK regulates and shuts down mTOR pathway for increased catabolism (increased glucose uptake, fatty acid oxidation) for cell survival, whereas mTOR is needed for cellular growth and proliferation (increased fatty acid and protein synthesis).

            During T-cell activation, there is increased uptake of glucose through the use of aerobic glycolysis. The enhanced uptake of glucose has been shown to be mediated and regulated in PI3K/AKT dependent manner, finally leading to the activation of mTOR pathway (14). T-cells can also utilize fatty acids for their energy needs, however, such utilization leads to the development of different lineages, such as memory CD8 T-cells and CD4 Tregs (15,16). Further upregulation of fatty acid synthesis (FAS) (mTOR pathway) and downregulation of fatty acid oxidation (AMPK pathway) of activated T-cells suggest that these two pathways are reciprocally regulated (17). AMPK inactivates Acetyl CoA carboxylase (ACC1 and 2) which is the rate limiting step for FAS (18). Blocking the FAS has been shown to interfere with the CD4 T-cells differentiation to effector T-cells and also in the reduction in peripheral frequencies of CD8 T-cells (19-21). Similarly, mTOR-deficient T-cells display strong bias towards the development of Tregs (22). All these data suggest that AMPK activation to enhance fatty acid oxidation could lead to inactivation of T-cells and enhance Treg lineage thereby reducing the inflammation mediated by T-cells.

            Apart from the role in T-cell compartment, mTOR pathway has also demonstrated to play a role in the skin microenvironment (23). MTOR inhibitor rapamycin treatment in a mouse model of atopic dermatitis led to reduced inflammatory cell infiltrate and reduced clinical score along with reduction in IgE levels (24).

      

 Discussion

            Targeting AMPK and mTOR pathway is a novel strategy to treat atopic dermatitis or eczema. Not only are both these pathways involved in T-cells but also in the skin microenvironment. However, the requirement of fatty acid oxidation to prevent activation of T-cells and FAS for activation is not completely compartmentalized. There is evidence suggesting that fatty acid oxidation may also be needed by T_H17 cells (21). Similarly Tregs may also need mTOR pathway activation towards their functional needs (21). There is some evidence in the cancer biology field that suggest that under some conditions AMPK pathway may not negatively regulate mTOR activation at all (28). Therefore combination therapies will work better than to target single pathway.

            Potential side effects due to systemic action of the AMPK activators or mTOR inhibitors could have repercussions on the therapy. However, most of the FDA-approved drugs have been shown to be tolerated well in humans. Moreover some drugs are available orally or for local topical application as well thus reducing potential side-effects.

            Atopic dermatitis on the other has been shown to have many different disease phenotypes (4). Some of the phenotypes are based on the difference in clinical features, prevalence and responses to treatments.  Therefore it may be necessary to tailor the treatment strategies empirically or systematically for better therapeutic outcomes.

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