Immunological effects of Aloe vera: a micro-review

Abstract

Currently, the use of Aloe vera has spread all over the world, as it has brought
many benefits throughout history thanks to its anti-ulcer, anti-cancer, anti-diabetic,
ant-oxidant and anti-inflammatory properties. Most of these properties converge in
the immunomodulatory effect that causes; this is one of the reasons why it is
necessary to discover the mechanisms involved in this effect. The purpose of this
micro-review is to perform a thorough analysis of in vitro or in vivo studies that
involve research on the immunomodulatory effect caused by A. vera.

1. Introduction

Aloe vera is a plant used for many centuries throughout history by different
civilizations and famous people; the name Aloe is derived from the Arabic "alloeh"
or Hebrew "halal" meaning bitter shiny substance [1]. It has been found that the
origin of this plant was in the south and east of Africa. There are more than 400
species found throughout the world, most grow in subtropical areas [2].

Normally, the part of the plant that is used is the leaf, morphologically it consists of
three parts: The crust, which is the outer layer, has the functionality of giving
protection to the matrix, there is carried out the synthesis of carbohydrates and
proteins; aloe latex, which is the fraction of the plant where most of its secondary
metabolites are concentrated, such as anthraquinones and glycosides; finally, aloe
gel, which is a transparent mucilaginous material that contains mainly water (99%),
its dry matter is constituted mostly long chain polysaccharides (55%), there are
also other components in minor proportions such as other short chain sugars
(17%), minerals (16%), proteins (7%), lipids (4%), phenolic compounds and a
variety of vitamins (1%) [2] [3].

Some of the particular components of the plant are already well characterized and
there is good knowledge about their activity, which as a result contributes to obtain
some of the properties for which the plant is known as: anti-ulcer effect, anti-cancer
activity, anti-diabetic effect, ant-oxidant effect and anti-inflammatory effect; thanks
to all these properties of A. vera its use is quite widespread all over the world [2].

Most of these properties are closely related to the immunomodulatory response

since the mechanisms converge, however, it is very problematic to make a
comparison in various studies and characterize each of the components according
to their immunomodulatory activity for different reasons, such as, some studies are
carried out with complex extracts that are not well characterized, in some others
studies with different species are carried out, so it is very difficult to make a
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comparison and an appropriate discussion [4], all this without mentioning the
complexity of the human immune system [5], but some in vitro and in vivo studies
can be collected to classify and advance research.

2. Immuno-modulating property
2.1 Wound healing and re-epithelialization properties of Aloe vera

The skin is the first protection barrier against the environment; it is the longest
organ of the human body and plays an important role in homeostasis and good
internal functioning. The skin is composed of two layers; the first layer is the
epidermis has been separated from dermis by the basal membrane and the
second layer is the dermis that takes place on subcutaneous adipose. Epidermis is
the outer layer of the skin, acts as a physical barrier against pathogens, toxins, and
harmful irradiation, it is mainly comprises keratinocyte layers in which some other
types of cells have spread including melanocytes and Langerhans cells. Dermis is
composed of papillary and reticular cells that comprise extracellular matrix or the
basal substance consisting of collagen, fibrous networks, elastin, and
glycosaminoglycan [6][7].

When there is trauma or damage to the skin, a series of cellular and molecular
processes are triggered to repair the damage. Wound healing consists of three
phases: thrombosis and inflammation, new tissue formation and tissue recovery.
The main cellular signaling events that take place in the healing process of a
wound are various growth factors, among which the most outstanding is the
fibroblast growth factor (FGF), the epidermal growth factor (EGF), the factor of
transforming growth (TGF) and insulin-like growth factor (IGF). Together, all these
factors contribute to the repair of the wound [6].

Since ancient times Aloe vera has been attributed healing properties in skin
wounds, but in recent years some mechanisms have been dispelled with which it
accelerates the repair of wounds. This healing property is associated with one of its
mannose-rich polysaccharides, called acemannan. Acemannan influences the
growth factor of fibroblasts, which stimulates the activity and proliferation of these
cells and also improves the production and secretion of collagen. A. vera not only
increases the amount of collagen at the site of the wound, but also increases the
cross-connects of the collagen, thereby accelerating the improvement of the wound
[6]. Other research has shown that β-sitosterol, which is a component of A. vera,
increases angiogenesis and has improved the healing of traumatic tissues by
increasing the rate of genetic expression of vascular endothelial growth factor
(VEGF) and its receptor at the site of injury [6].

2.2 Burn healing

Aloe vera is considered effective for the healing of burn wounds. There is evidence
that shows a shortening in the duration of wound healing from first to second
degree burns and an increase in the success rate of healing, this thanks to the

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application of A. vera. Some studies report that some extracts of A. vera improve
the reestablishment of vascularization and allow a faster recovery of tissues
damaged by burns; these results may be due to several mechanisms that include
an increase in the synthesis of collagen and in the rate of epithelization due to the
effect of acemannan to stimulate the fibroblasts. The rapid recovery could also be a
consequence of the anti-inflammatory, antimicrobial and hydrating effects attributed
to A. vera [8][9].

Regarding the safe use of A. vera, it should only be taken into account that for its
topical use it is important to reduce the anthraquinones, in some studies they were
a potential cause of irritation [8].

2.3 Interaction of Aloe vera with the immune system at the cellular level:
in vitro and in vivo studies.

The manipulation of the immune system is important for the treatment of a variety
of diseases. It has been reported that extracts of the Aloe vera leaf have
immunostimulant and immunosuppressive activity in some cells of the immune
system. Most studies on the immunomodulation of A. vera focus on its
polysaccharide acemannan, it is believed that its immunostimulating effects are
due to the activation of macrophages and the processing of the antigen. Activated
macrophages secrete cytokines including IL-1β, IL-6, interferon and TNF-α in vitro
[10][4].

Acemannan also improves the sensitivity of macrophages to IFN-γ, inducing

apoptosis. Neither acemannan nor IFN-γ alone was able to induce apoptosis. Both
are necessary, this synergistic effect seems to work by inhibiting the expression of
Bcl-2 proteins [10].

Some studies have also highlighted the immunomodulatory properties of the

smaller phenolic components of Aloe leaves. Aloe emodin and other anthraquinone
derivatives have an immunosuppressive effect by blocking the proliferation of
lymphocytes. Aloe emodin also reduced the expression of IL-1β, IL-2 and IL-2
receptors. It has been suggested in various studies that aloe emodin suppresses
both macrophages and lymphocytes. Other studies have identified 37 other
anthraquinones with the ability to block the induction of cytolytic T lymphocytes and
prevent the production of antibodies [10] [4].

2.4 Aloe vera in inflammation

Inflammation is a response of the body to different types of injuries. It is not just an

isolated event, but involves a complex sequence of metabolic events unleashed by
a wide variety of injuries such as burns, wounds, bites, stings, etc. Inflammation is

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characterized by a wide variety of symptoms that include swelling, redness,
warmth and pain. These symptoms are a consequence of vasodilatation and
increased permeability of the membrane, which allows the migration of leukocytes
[11].

Β-sitosterol is the most abundant phytosterol in aloe extracts. Β-sitosterol

stimulates smooth muscle cells to release prostacyclin. However, treatment with β-
sitosterol blocks the release of PGI2 and prostaglandin E2 (PGE2) from
macrophages. Therefore, treatment with β-sitosterol is expected to affect
vasodilation and have a therapeutic effect on inflammation. Aloesin from the foliar
chromium of aloe and its derivatives inhibit the synthesis of cyclooxygenase-2 and
thromboxane A2 through its antioxidant activities. Thus, Aloe vera chromones have
anti-inflammatory effects. In contrast, it has been shown that anthraquinones
stimulate the release of PGE2 and, therefore, could be expected to be pro-
inflammatory [9].

Chemotactic factors including several proteins and peptides are required to

increase cell motility, especially the motility of leukocytes during inflammation.
Blocking these chemotactic factors prevents inflammation. Several compounds in
the extracts of A. vera are capable of blocking chemotaxis. Anthraquinones
suppress cytolytic T lymphocytes in favor of suppressor cells. In addition,
anthraquinones decrease the production of cytokines and the expression of IL-2
mRNA in activated T lymphocytes, which decreases chemotaxis. More recent
studies have shown that aloe emodin decreases the plasma levels of the cytokines
IL-2 and TNF-α while increasing IL-10 (which in turn downregulates the activity of
the cytokines IL-2 and TNF-α). The exposure of acemannan stimulates the
production of cytokines and activates lymphocytes. Specifically, it has been shown
that pure acemannan isolated from the leaves of A. vera stimulates macrophages
to release IL-1, IL-6, interferon-γ and TNF-α in vitro. Processed products of A. vera
have also been shown to have a decrease in pro-inflammatory cytokines (IL-1β, IL-
6 and TNF-α) and an increase in the anti-inflammatory cytokine IL-10 in in vitro
studies [12][13]. A decrease in IL-1β has also been demonstrated by a decrease in
NLRP-3 inflammosome expression, as well as its signaling and decreased
expression of multiple receptors [12]. Similarly, A. vera lectins stimulate cytokine
production. It has been shown that Aloctin A, the best characterized of Aloe lectins,
stimulates the production of IL-2 and increases the production and activation of
macrophages. Therefore, extracts of A. vera contain stimulant compounds and
chemotactic inhibitors. The chemotactic effect of the extracts of A. vera would
depend, therefore, on the levels and proportions of the factors that affect the
chemotaxis, as well as on its redox state. The extract of aloe leaves contain
multiple active phytochemicals. It is likely that several of these are required to

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control different phases of the inflammatory process. Failure to consider this is
probably responsible for past ambiguities about the effectiveness of aloe extracts
as anti-inflammatory agents [9].

3. Conclusion

Currently, Aloe vera has an extensive industrial application throughout the world,
since its components are compatible with the manufacture of many products; it is
used mainly in food industry, pharmaceutical industry and cosmetics industry [14].
For this reason it is very important to have a better knowledge of the plant. The
immunomodulatory effect is a subject which does not yet have all the answers. It is
necessary to carry out more studies where the mechanisms that Aloe vera exerts
with greater precision are discovered.

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