The Immunomodulatory Effect of Alpha-Lipoic Acid

Review Article
The Immunomodulatory Effect of Alpha-Lipoic Acid in
Autoimmune Diseases

Wei Liu ,

1 Lian-jie Shi,2 and Sheng-guang Li 2

Department of Respiratory and Critical Care Medicine, e 900th Hospital of the Joint Logistic Support Force, PLA,
Fujian Medical University, Fuzhou 350025, China
Department of Rheumatology and immunology, Peking University International Hospital, Beijing 102206, China
Correspondence should be addressed to Sheng-guang Li;
Received 10 September 2018; Revised 11 February 2019; Accepted 21 February 2019; Published 20 March 2019
Academic Editor: Hai-Feng Pan
Copyright © 2019 Wei Liu et al. Tis is an open access article distributed under the Creative Commons Attribution License, which
permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Αlpha-lipoic acid is a naturally occurring antioxidant in human body and has been widely used as an antioxidant clinically.
Accumulating evidences suggested that �-lipoic acid might have immunomodulatory efects on both adaptive and innate immune
systems. Tis review focuses on the evidences and potential targets involved in the immunomodulatory efects of �-lipoic acid. It
highlights the fact that �-lipoic acid may have benefcial efects in autoimmune diseases once the immunomodulatory efects can
be confrmed by further investigation.

1. Background
Αlpha-lipoic acid (ALA) is a naturally occurring dithiol
compound that is wildly synthesized in the mitochondrion by
plants and animals. Physiologically, ALA is a cofactor for �-

ketoglutarate dehydrogenase complex to protect mitochon-
dria from oxidative attack.

ALA and dihydrolipoic acid (DHLA) are the oxidized
form and reduced form of LA, respectively. Tey are a pair of
powerful redox couple which can directly scavenge reactive
oxygen species (ROS), chelate metals, and regenerate other
antioxidants to show antioxidant biochemical properties.
With both liposoluble and water-soluble dual properties,

ALA and DHLA can fully function intracellularly and extra-
cellularly [1, 2].

Based on its cogent antioxidant properties and proven
safety, ALA has been widely used to treat oxidative stress
associated diseases, such as diabetes, neurological diseases,
and cardiovascular diseases. More and more studies on LA
had been performed; better understanding had been achieved
towards the mechanisms of molecules, including the fact that
ALA stimulated glucose uptake in insulin-sensitive cells and
enhanced both the antioxidant defenses and the function
of endothelial vascular cells [3]. Several lines of evidence
suggested that ALA might have immunomodulatory efect.

With the progress of investigation of basic and clinical
immunology, the role of oxidative stress on the pathogenesis
of some autoimmune diseases has been generally recognized
and interaction of ROS with the immune system well proven.
On one hand, ROS may have a physiological role in signal
transduction of all kinds of immune cells. For example,
macrophage produced ROS to kill bacteria and regulatory T
cells (Treg) released ROS to suppress activation of other T
cells [4]. On the other hand, in pathological status, immune
cells produce excessive ROS which exacerbated infammation
and broke balance in the immune system. For example,
oxidative stress was one of the contributors to immune system
dysregulation and dysfunction [5], which in turn led to
deteriorate oxidative stress in systemic lupus erythematosus
(SLE) [6, 7]. Both oxidative stress and immune dysfunction
participated in the development and progression of SLE.

Recently, redox-controlled activation of the mechanistic tar-
get of rapamycin (mTOR) has been recognized to play a

critical regulatory role in the immune system [8], which
highly implies that mTOR is a key bridge of metabolic stress
and autoimmunity. It can be speculated that the antioxidant
may be used for the treatment of certain autoimmune diseases
based on evidence that ROS clearance played a role in
immune regulation. Here in, we summarize the evidence

BioMed Research International
Volume 2019, Article ID 8086257, 11 pages

2 BioMed Research International
of the immunomodulatory efects of ALA and possible
mechanisms involved by literature review.
1.1. e Involved Signaling Pathways of ALA

1.1.1. IKK�, Ras/Erk1/2, and PI3K/Akt/mTOR Signaling Path-
ways. Te mTOR, which could drive expansion of plas-
mablast [9] and T follicular helper (Tf) cells [10], induce

the diferentiation of T1 and T17 [11], and restrict the
diferentiation of Treg [12] and CD8 memory T cells [13], is
an essential mediator of immunity.
ALA had been shown to regulate upstream kinases of
mTOR in multiple pathological conditions [1].

ALA blocked TNF-� induced IKK/NF-�B signaling cas-
cades in RA-FLS and human umbilical vein endothelial cells

(HUVECs) [14, 15]. TNF-� activated mTORC1 pathway via
IKK� activation in tumor angiogenesis and insulin resistance
[16, 17].Terefore, it can be speculated that ALA may suppress
IKK�-mediated activation of mTORC1.
ALA inhibited Erk signaling to improve atherosclerotic

lesions and inhibit vascular smooth muscle cells prolifer-
ation [18]. ALA also inhibited activation of Erk mediated

by 5-hydroxytryptamine (5-HT) [19] and epidermal growth
factor (EGF), basic fbroblast growth factor (bFGF), and
platelet-derived growth factor (PDGF) [20]. Te activation
of Akt/S6K1 and Erk suppressed by ALA attenuated hepatic
stellate cell activation and ROS generation stimulated by
TGF-�/PDGF [21].
However, Erk signaling activated by ALA has been

reported to protect cardiovascular system and nervous sys-
tem. ALA increased heme oxygenase-1 (HO-1) to protect vas-
cular smooth muscle cells [22], ameliorated glucose/glucose

oxidase- (G/GO-) induced injury of rat cardiomyoblast

[23], inhibited adipocyte diferentiation [24], protected cor-
tical neurons from 4-hydroxy-2-nonenal- (HNE-) mediated

oxidative damage and neurotoxicity [25], and promoted
neurite outgrowth via activation of Erk [26].
Te efect of bidirectional regulation of Erk1/2 kinases on
mouse fbroblasts mediated by ALA was dependent on the
cell culture medium containing serum or not [27, 28], which,
to some extent, can interpret the fact that ALA regulated the
same kinase in diferent directions in diferent pathological
ALA activated Akt kinase to protect pancreatic beta cells
from hydrogen peroxide-mediated oxidative stress [29]. In
rat L6 muscle cells, ALA mitigated insulin resistance via Akt
activation and Erk inhibition [30].

ALA enhanced apoptosis and suppressed cell prolifera-
tion of human breast cancer cell line [31]. ALA also induced

hepatoma cells apoptosis [32] to exert antitumor efects by
suppression of PI3K/Akt pathway. ALA also inhibited leptin
production of adipocytes and ameliorated insulin resistance
of Goto-Kakizaki (GK) rat to improve disorders of glucose
and lipid metabolism [33, 34].
Cytoprotective efect of ALA also could be mediated

through phosphorylation of Akt kinase to ameliorate endo-
plasmic reticulum stress-induced FRTL5 thyroid cell death

[35], protect neurons from injury induced by bupivacaine,

amyloid and hydrogen peroxide [36, 37], reduce ischemia-
reperfusion injury [38, 39] and oxidative stress injury of rat L6

muscle cells induced by TNF� and palmitate [30], decrease
hydrogen peroxide-induced apoptosis of pancreatic beta
cells [29], attenuate LPS-induced cardiac dysfunction [40],
monocyte activation, and acute infammatory responses [41],
and ameliorate vascular endothelial dysfunction [42, 43].
1.1.2. AMPK Signaling Pathway. ALA has been reported
to activate AMPK to upregulate adipose triglyceride lipase
(ATGL) to reduce body weight and visceral fat content of
diabetic mice [44].
Trough AMPK/mTORC1/S6K1 signaling pathway,
leucine and glucose induced insulin resistance which

could be attenuated by ALA via TSC2-mTOR inhibitors-
phosphorylation [45, 46] and AMPK activation [47] in

skeletal muscle. ALA also activated AMPK to downregulate
expression of S6K1 [48] leading to inhibition of insulin
secretion in pancreatic beta cells, which implies involvement
of mTOR.

However, ALA was also reported to inhibit the phospho-
rylation of AMPK, which suppressed appetite and prevented

obesity in the hypothalamus [49–51] consistent with the efect
of ALA on peripheral tissue to improve insulin resistance and
decrease lipid accumulation and lipogenesis.
Overall, ALA regulated some upstream kinase of mTOR
in inconsistent directions in diverse cell types of diferent
diseases. It has been proven that mTOR can modulate T cell
diferentiation and inhibit Treg cells which are defcient in
SLE patients [52, 53]. N-acetylcysteine (NAC), a well-known
antioxidant, has been reported to inhibit mTOR in vitro [54]
and improve the outcome of murine lupus [55] and even SLE
patients [56]. It has also been observed that disease activity
could be reduced and Treg populations could be reversed by
mTOR blockade in treating SLE patients [57]. Although these
existing indirect evidence was tempting to conclude that ALA
had efect on regulation of mTOR signaling, regulation of the
mTOR pathway by ALA in immune cells is worthy of further
investigation for patients with autoimmune diseases of high
relapse rate and poor responsiveness to traditional treatment.
2. Effects of ALA on Immune System
Te proven efects of ALA on adaptive immune cells,
including T and B cells, are briefy summarized in Table 1
and Figure 1, and the proven efects on innate immune
cells including NK cells, macrophages, and monocytes are
summarized in Table 1, all of which will be discussed in detail
2.1. Effects on Adaptive Immune Cells
2.1.1. Effects on T Cells. Multiple sclerosis (MS) is an
autoimmune disease in central nervous system, which is
characterized by the migration and the long-term survival
of myelin-specifc T lymphocytes into the central nervous
system (CNS). A common model of MS is experimental
autoimmune encephalomyelitis (EAE). Studies demonstrated
the benefcial efects of ALA on treating EAE by suppressing

BioMed Research International 3

Table 1: Evidence of ALA on adaptive immune cells.

T cell B cell

Animal model


Decrease the number of T17 and T1 in

Increase Treg numbers in spleen;
Reduce migration.

High fat diet mice

Recover transcriptional levels of the
diferentiation-related genes of jejunal T


Restore transcriptional levels of BCR signaling
pathway relating genes;
Decrease the apoptotic percentage of splenic B


Atopic dermatitis Suppress production of IFN-� and IL-4

by CD4+T. Reduce total serum IgE levels.

Models of established

Reduce T cell migration in response to

Endotoxemia mice Increase the number of splenic B cells.



Increase the number of T cells;
Improve the lymphocyte proliferation


Ameliorate the impaired mitochondrial
function of CD4+T cells.
Advanced cancer Induce lymphocyte progression from
G0/G1 to S phase.
Jurkat T cells Inhibit NF-�B activation induced by TNF
Reduce migration.

Normal human

Increase cAMP which afects
proliferation and activation of T cells;
Down-regulate the expression of CD4
Reduce migration.

ALA: �-lipoic acid.
EAE: experimental autoimmune encephalomyelitis.
T17: T helper cell 17.
T1: T helper cell 1.
CNS: central nervous system.
Treg: regulatory T cells.
BCR: B-cell receptor.
IFN-�: interferon-�.
AIDS: acquired immunodefciency syndrome.
NF-�B: nuclear factor kappa B.
TNF: tumor necrosis factor.
cAMP: cyclic adenosine monophosphate.

the infltration of infammatory cells [58–61]. Recently, Wang
and colleagues [60] reported that ALA reduced the number
of T17 and T1 cells in CNS and increased the number
of splenic Treg cells in EAE mice. It highly implied that
ALA showed immunomodulatory efects on diferentiation
and proliferation of T cells. ALA has also been reported to
increase cAMP synthesis through activation of prostaglandin
receptors (EP2 and EP4) in peripheral blood T cells [62]
(Figure 1, A). Te elevated levels of intracellular cAMP
decreased the expression of IL-2 and IL-2R� (CD25) [63]
(Figure 1, B), which in turn afected proliferation and
activation of T cells [64].
More studies indicated that ALA could regulate function
of T cells in many ways. ALA could ameliorate the impaired

mitochondrial function of CD4+T cells of acquired immun-
odefciency syndrome (AIDS) patients [65], downregulate

the expression of CD4 molecules of human peripheral blood

T cells [66], inhibit nuclear factor kappa B (NF-�B) activation
induced by tumor necrosis factor-alpha (TNF) in Jurkat T
cells [67] (Figure 1, C), suppress production of interferon-
� (IFN-�) and interleukin-4 (IL-4) (Figure 1, D) by CD4+T
cells to reduce the severity of atopic dermatitis lesions in mice
model [68], and induce lymphocyte progression from G0/G1
to S phase (Figure 1, E), which might be related to restore the
function of immune system in advanced cancer patients [69].
Besides efects on T cell proliferation, diferentiation,
and the cytokines produced by them, ALA could also
inhibit migration of T cells. Ying and colleagues found that
ALA could directly reduce T cell migration in response
to chemokines to reduce T cell numbers in atherosclerotic
plaque in models of established atherosclerosis [70]. ALA
was also reported to reduce migration of T cell [58, 71],
lymphocyte and monocyte of models of MS [61], and Jurkat
T cells [72], which were associated with downregulated

4 BioMed Research International







1 1 1 1






mPTP opening ROS

Nrf2 sMaf



Ribosomal biosynthesis
mRNA biosynthesis
G1 to S phase traverse




ATP depletion




Indirectly activates
Indirectly inhibits
Unknown relationship








Figure 1: Effect of ALA on T cell. A ALA increase cAMP synthesis through activation of prostaglandin receptors (EP2 and EP4) in peripheral
blood T cells. B Te expression of IL-2 and IL-2R� (CD25) could be inhibited when the level of cAMP was increased by ALA. C ALA could

inhibit NF-�B activation induced by TNF in Jurkat T cells. D ALA could suppress production of interferon-� (IFN-�) and interleukin -4 (IL-
4). E ALA could induce lymphocyte progression from G0/G1 to S phase. F ALA was also reported to reduce migration of T cell, lymphocyte

and monocyte of models of MS, and Jurkat T cells, which were associated with down-regulated expression of very late activation-4 antigen
(VLA-4). G Uncontrolled mPTP opening leads to decrease Ψm irreversibly until dissipation which results in apoptosis and necrosis of
cells. H Persistent MHP in SLE T cells could enhance ROS production. 0 Studies showed that ALA and DHLA promoted mPTP opening
in mitochondria of rat liver. 1 mTORC1 was a central common regulator of a complex signaling network In cytoplasm, in which Ras/Erk,
PI3K/Akt, and IKK� activated mTORC1 while Dsh/GSK3 and LKBl/AMPK inactivated mTORC1. 2 Activated mTORC promoted protein
synthesis by phosphorylating the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and p70 ribosomal S6 kinase 1 (S6K1).

expression of very late activation-4 antigen (VLA-4) (Figure 1,
F) and inhibition of MMP-9 activity by ALA [72].

2.1.2. Effects on B Cells. Te studies showed that ALA supple-
ment might play a role in high fat diet mice to prevent the

development of oxidative stress and to attenuate B-cell injury
by increasing the gene expression of the B-cell receptor (BCR)

signaling pathway and decrease the apoptotic percentage of
splenic B lymphocytes [73], which was also relevant to the
improvement of gene expression level of BCR [74]. It has been
proven that ALA increased the number of splenic B cells in
endotoxemia mice [75] and reduced total serum IgE levels of
atopic dermatitis mice model [68].Tese experiments suggest
that ALA plays a regulating role on proliferation, apoptosis
and function of B cells (Table 1).

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Table 2: Evidence of ALA on innate immune cells.
NK cell Macrophage Monocyte


EAE Inhibit the phagocytosis of

Decrease monocytes infltration
into the CNS.

High fat diet

Suppress infltration and
activation of macrophage to
attenuate visceral adipose

RAW 264.7

Decrease the production of
MCP-1 and TNF-� induced by


Increase cAMP
production to
suppress cytotoxicity
and IFN-�

Induce the expression of HO-1 by


ALA: �-lipoic acid.
NK cell: natural killer cell.
EAE: experimental autoimmune encephalomyelitis.
CNS: central nervous system.
BMDM: bone marrow-derived macrophages.
MCP-1: monocyte chemotactic protein 1.
TNF-�: tumor necrosis factor-alpha.
LPS: lipopolysaccharide.
cAMP: cyclic adenosine monophosphate.
IFN-�: interferon-�.
HO-1: heme oxygenase-1.
Nrf2: nuclear factor-erythroid 2-related factor.

2.1.3. Effects on Innate Immune Cells
Natural Killer Cell (NK Cell), Macrophage, and Monocyte
(See Table 2). Cytotoxicity and cytokines secretion are two
main functions of NK cells. Te former is associated with
the release of granzymes (perforin and proteases) from their
cytoplasm. INF-� secretion is a representative of the latter.

INF-� is a potent macrophage activator for both phagocy-
tosis and lysis. IFN-� secretion induced by IL-12/IL-18 and

cellular cytotoxicity in NK cells could be inhibited by ALA,
which increased cAMP production via G protein-coupled
receptors- (GPCRs-) dependent and GPCRs-independent

mechanisms [62, 76, 77]. In addition, it has also been demon-
strated that both cAMP and cAMP-inducing agents (PGE1,

theophylline, and histamine) suppressed cytolytic function
of NK cells [78]. PGE2, another cAMP elevating agent, also

suppressed cytotoxicity and IFN-� production induced by IL-
15 [79]. Terefore, ALA could suppress NK function in a few

It has also been found that ALA regulated activation,
phagocytosis, and migration of macrophage by either direct
or indirect means. ALA inhibited the phagocytosis of myelin
by macrophages [80], which was the main autoantigen in EAE
mice, and decreased the production of monocyte chemotactic

protein 1 (MCP-1) and TNF� induced by lipopolysaccha-
ride (LPS) of macrophages [81, 82]. Also, ALA decreased

monocytes infltration into the CNS and stabilized brain
endothelial cells in EAE rat [61], which might be associated
with the downregulated intracellular adhesion molecule-1
(ICAM-1) expression of monocytes [83] and the upregulated

vascular cell adhesion molecule-1 (VCAM-1) expression of
endothelial cells [84]. In addition, ALA could induce the

expression of heme oxygenase-1(HO-1) by nuclear factor-
erythroid 2-related factor 2 (Nrf2) in human monocytic cells

3. Other Potential Targets of ALA
Immunomodulatory Effects
ALA has been widely used for decades in clinic and studied
in various experimental models. Terefore, we found the
potential targets for immunomodulatory efects of ALA in
these researches.

3.1. Mitochondrial Membrane Potential (Ψm). Mitochon-
dria provide place for the citric acid cycle and oxidative

phosphorylation, which is the energy station of cells and
is involved in cell diferentiation, cell cycle regulation, and

cell death. Te stability of Ψm is essential for the mainte-
nance of normal physiological function of cells. Te electron

transport chain and the F0F1-ATPase complex maintain an
electrochemical gradient namely “Ψm”, and vice versa,
Ψm tightly regulates the production of ROS and ATP
synthesis [86]. Mitochondrial permeability transition pore
(mPTP) is a series of protein channels which are located
in the inner and outer mitochondrial membrane. mPTP
closes completely to stabilize Ψm whereas mPTP opens
transiently to a low conductance state to result in lowering
Ψm. Uncontrollable mPTP opening leads to decrease Ψm

6 BioMed Research International
irreversibly until dissipation which results in apoptosis and
necrosis of cells [87, 88] (Figure 1, G). In the process of
both activation and apoptosis of T lymphocytes, Ψm was
transiently reversibly elevated, that is what mitochondrial
hyperpolarization (MHP) in physiological status should be
[89]. However, persistent MHP in T cells of SLE patients
would enhance ROS production (Figure 1 H), which resulted
in activation of macrophages [90] and dendritic cells [91]
to exacerbate infammation [92, 93] and resulted in ATP
depletion which increased IL-10 production and spontaneous
apoptosis of T cells [94]. T cell apoptosis not only provided
a source of nuclear antigens but also was correlated with

SLE disease activity [95, 96]. Increased production of IL-
10 could promote T cell apoptosis [97] and contribute to

the production of autoantibodies by hyperactive SLE B
lymphocytes [98, 99]. Tere were proofs showing that ALA
and DHLA promoted mPTP opening of mitochondria in rat
liver [3, 93, 100] (Figure 1, 0). Tus, the authors speculate
that ALA may attenuate mitochondrial dysfunction in SLE
from several aspects. ALA opens mPTP to reduce ΔΨm,
which improves pathological MHP of SLE T cells and directly
quenches ROS to correct dysfunction of T cells and B
3.2. Neutrophil Extracellular Traps (NETs). Neutrophils play
a very important role in innate immune system and are the
frst leukocytes to be recruited to the site of infection to
eliminate pathogens by multiple mechanisms which include
phagocytosis, infammatory mediators secretion, and NETs
release which is also known as NETosis. NETs are composed
of nucleic acids, histone proteins, and granule proteins with
or without death of neutrophils [101]. NETs only fght against
pathogens but also have been implicated in pathogenesis of
the autoimmune diseases (e.g., SLE [102, 103], RA [104, 105],
psoriasis [106], and autoimmune small-vessel vasculitis [107])
and thrombosis [108]. Nuclear material of NETs components
became autoantigens afer it was extruded from the cell
to induce autoantibodies production [109]. NETs formation
was dependent on autophagy and ROS generation [110, 111]
and regulated by mTOR signaling pathway [112, 113]. It

has been speculated that ALA may be capable of quench-
ing ROS and regulating mTOR signaling, which suggests

that it may have benefcial efects on NETs formation to
reduce the autoantibodies production and protect vascular
3.3. Nrf2 Signaling Pathway. ALA is well recognized to
be an activator of Nrf2 signaling [1, 114]. Te nuclear
factor-erythroid 2-related factor 2 (Nrf2), a central regulator
of cellular resistance to oxidant stress, binds antioxidant
response element (ARE) to regulate expression of a lot
of ARE-containing genes to play a pivotal role in control
of oxidant homeostasis [115]. Tere is a little evidence to
show association between Nrf2 signaling and pathogenesis
of autoimmune disease. It has been demonstrated that Nrf2-
defcient female mice developed severe nephritis similar to
lupus [116] and Nrf2 gene variant was relevant with nephritis

in childhood-onset SLE patients [117]. Nrf2 (-/-) mice devel-
oped regenerative immune-mediated hemolytic anemia [118]

and disruption of Nrf2 aggravated [119] while activation of
Nrf2 attenuated [120] neuroinfammatory disorders in EAE.
Hence, ALA may have regulatory efects in immune system
via Nrf2 pathway.
4. Safety of ALA
ALA, a naturally occurring antioxidant in human body and
available from common dietary sources, has been used to
treat diabetic neuropathy and retinopathy for over 50 years
in Germany. A number of clinical trials have reported that
oral LA supplementation up to 2400 mg/d and intravenous
LA supplementation up to 600 mg/d for three weeks showing
no adverse efects versus placebo [1, 2]. Moreover, fexible
regulatory efects of ALA have been shown by Sen and
colleagues that ALA promoted apoptosis induced by Fas

in Jurkat cells but not healthy peripheral blood lympho-
cytes [121]. Te data of these studies supports the safety of

5. Summary
In conclusion, ALA, a natural ingredient of human body,
not only acts as a powerful antioxidant but also is able to
regulate the immune system in either direct or indirect ways.
Studies reviewed above might suggest that ALA is used to
treat autoimmune diseases including SLE, RA, and primary
vasculitis as well as MS. Te current therapies for systemic
rheumatic diseases are efective. However, there was still a
high percent of patients with not enough or no response to
the therapies. Terefore, if the immunomodulatory efects
of ALA could be confrmed by further investigation, it
might have benefcial efects in conjunction with the current
treatment of rheumatic diseases.
Conflicts of Interest
Te authors declare that they have no conficts of interest.
Authors’ Contributions
Wei Liu and Lian-jie Shi contributed equally to the paper.
Te authors acknowledge Guo-xiang Lai, M.D., from the
900th Hospital of the Joint Logistic Support Force, PLA,
for his contribution to the fgure drawing and medical
writing assistance while drafing this manuscript.Tis work is
supported by grants from Fuzhou General Hospital (2018 J05)
and Clinical Key Specialty Construction Project in Fujian
Province (Min Wei Medical Letter [2015] no. 593).

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