Upon activation, native CD4+ T cells have the capacity to differentiate into two major subsets of T helper cells known as Th1 and Th2
[35][32]. Th1 cells contribute to cellular immunity, promote the killing efficiency of macrophages and stimulate the proliferation of CD8+ T cells. On the contrary, Th2 cells play a role in humoral immunity by stimulating the proliferation of B-cells and facilitating Abs class switching in B-cells
[10,36][10][33]. It has been proved that the RAS may be involved in promoting Th1-mediated AI diseases
[37][34]. Ang II has been found responsible for disrupting the Th1/Th2 balance by promoting the production of Th1 cytokine IFN-γ, thereby exerting pro-inflammatory effects, while reducing the levels of the Th2 cytokine IL-4
[38][35].
Tregs are tissue resident memory cells (TRM), which constitute approximately 20–40% of the CD4 T-cells in both human and mice skin. Their primary function is to uphold the immune homeostasis of the skin, facilitate wound healing and participate in tissue repair. These cells play an important role in chronic inflammatory conditions affecting the skin, such as psoriasis and vitiligo.
5.2. Dendritic Cells
4.2. Dendritic Cells
Dendritic cells (DCs) are specialized APCs that have a critical role in regulating the innate and also the adaptive immune responses
[40,41][36][37].
In a study by Meng et al.
[40][36], it was observed that Ang II exerts contrasting effects on DCs. On one hand, Ang II inhibits the phagocytic activity and proliferation of DCs. However, on the other hand, it promotes the maturation and the migration of DCs and also the expression of pro-inflammatory cytokines. Additionally, Ang II stimulates the T cell proliferation mediated by DCs
[40][36].
5.3. Macrophages
4.3. Macrophages
Macrophages and their precursors, known as monocytes, are white blood cells specialized in clearing away cellular debris and pathogens through phagocytosis. Additionally, they possess the ability to trigger and activate other immune cells to respond to invading pathogens
[14].
Aldosterone aims at monocytes/macrophages and promotes the activation/migration of these cells in the ECs by increasing the expression of VCAM-1 and ICAM-1
[41][37].
It was proven that the activity of AT1R in M1 macrophages promotes polarization, which accelerates the inflammation with progression of tissue damage
[42][38]. Likewise, Ang II upregulates the expression of monocyte chemoattractant protein-1 (MCP-1) and one of its receptors, CCR2
[14,43][14][39].
5.4. Neutrophils
4.4. Neutrophils
PMNs, as the first responding cells to invading pathogens, play a crucial role in providing early immune protection. PMN bactericidal activity is increased by ACE present within them, regardless of the involvement of the Ang II/AT1R pathway. By interacting with AT1R, Ang II releases IL-8, which stimulates PMN recruitment and infiltration. Also, when stimulated by Ang II, PMNs produce oxidative bursts
[10,44][10][40].
Cathepsin G (CatG), found in macrophages and PMNs, is a lysosomal protease that is upregulated in response to signals linked to infection and inflammation. CatG can elevate the local generation of Ang II by converting both angiotensinogen and Ang I to Ang II
[10,45,46][10][41][42].
65. RAS in the Skin
New research findings have unveiled the presence of a local RAS within the skin, where ACE has a role in the regulation of inflammation and autoimmunity
[47][43]. The components of the RAS are situated in cutaneous and subcutaneous layers. They are crucial in various skin-related conditions, such as inflammation, fibrosis, scar formation and certain types of skin cancers
[48][44].
Components of RAS are expressed in the human skin. Initial studies highlighting the presence of a local RAS in the skin revealed that skin cells, particularly keratinocytes, possess the ability to produce Ang II (as well as potentially other angiotensins) independently of the systemic circulation’s supply of RAS components. Keratinocytes are abundant in AT1R throughout all epidermal layers. AT1 receptors are also expressed in the hair follicles and sweat glands. In dermis, fibroblasts express AT1R, AT2R, MAS, angiotensinogen, renin, ACE, Ang II, and mast cells express chymase. In hypodermis, the subcutaneous fat expresses the same components of RAS as in dermis plus ACE2
[49,50,51][45][46][47].
RAS activity is involved in cell proliferation, differentiation, tissue remodeling and skin photoaging
[52,53][48][49]. Stimulation of AT1R triggers cellular processes, including cell proliferation, migration, collagen synthesis and angiogenesis. Contrarily, the AT2R inhibit these actions by blocking the synthesis of certain pro-inflammatory molecules, like TGF-β, TNF-α and IL-6. Therefore, the interplay between AT1R and AT2R within RAS provides a fragile balance in regulating these cellular functions and inflammatory responses in the skin
[54][50].
The expression of RAS components is upregulated in human wounded skin. Ang receptors have been implicated in wound healing and scar formation of the skin (
Figure 4)
[49][45]. Impaired wound healing has been associated with disruptions in the function of AT1R. In both aging and diabetes, RAS dysregulation occurs, characterized by high AT1R expression and low AT2R expression. This modification in the AT1R/AT2R ratio is linked with a reduction in epidermal thickness, collagen degeneration, dermal layer fractures and subcutaneous fat atrophy
[55][51]. Research studies revealed that valsartan (an ARB) exhibits the highest level of skin penetration among other ARBs. Topical application of 1% valsartan gel has shown significant enhancement in wound healing. Researchers found that the rate of wound healing is superior while using topical valsartan compared to losartan. The beneficial effects of valsartan gel were mediated through the activation of AT2R, as the healing effect was absent in mice lacking AT2R. Conversely, the application of a 5% captopril gel resulted in a notable delay in the process of wound healing
[48][44].
Figure 4. The role of RAS in the wound healing process. AT1R promotes inflammation, proliferation, angiogenesis and pain. AT2R and MR promote remodeling and differentiation and decrease inflammation and proliferation. MasR increases proliferation and angiogenesis and decreases inflammation (adapted after
[49][45])
Hypertrophic and keloids scars are characterized by an aberrant wound healing process that results in excessive ECM production. There is evidence that both Ang II and AT1R concentrations are elevated in keloid and hypertrophic scars compared to normal skin. AT1R promotes scar formation. In hypertrophic and keloid scars, the AT1R activation leads to increased ECM production, transition of fibroblasts into myofibroblasts and contraction of granulation tissue. This process involves the activation of TGF-β signaling pathways. Elevated levels of Ang II, acting through AT1R, contribute to skin scar formation by upregulating the expression of inflammatory molecules (e.g., IL-6, VEGF, TGF-β1)
[48,51,54][44][47][50].
ACEIs reduce scar formation, inhibit fibroblast proliferation, and suppress the expression of TGF-β1 and collagen. TGF-β1 has cytoprotective effects in mitigating tissue injury through promoting wound repair, tissue regeneration and exerting anti-inflammatory effects. Abnormal TGF-β1 signaling can cause pathological fibrosis in response to tissue injury
[56,57][52][53]. Moreover, the dysregulation between pro-inflammatory (IL-6) and anti-inflammatory (IL-10) cytokines can lead to hypertrophic scarring. In a study by Hedayatyanfard et al.
[54][50], a 5% topical ointment losartan was investigated as a treatment for hypertrophic and keloid scars. The results showed that the application of losartan ointment led to significant improvements, including vascularity, pigmentation, pliability and height; at the end of treatment period, scars were smaller.