Dermal macrophage
Dermal macrophages are
Thus, the exact contribution of each phenotype to cancer defence and the skin's homeostasis is still unclear.Dermal
Dermal macrophages belong to the
Development
Dermal macrophages are either from embryonic progenitors or circulating progenitors. Numerous dermal macrophages are present in the skin at birth due to the infiltration of yolk-sac derived macrophages and
Prenatal development
The prenatal portion of tissue-resident dermal macrophages is produced from yolk-sac derived precursors.[8] The generation of dermal macrophages results from primitive haematopoiesis or definitive haematopoiesis.
Primitive haematopoiesis allows the generation of yolk-sac derived macrophages and subsequent release into the foetal bloodstream for tissue infiltration and colonisation. The infiltration of the skin by yolk-sac derived macrophages occurs as soon as 8.5 days after fertilisation. Different gene expressions regulate this process. It is independent of the
Definitive haematopoiesis occurs from 11 days and onwards after
The level of dermal macrophages from prenatal development remains detectible through constant, slow proliferation.
Postnatal development
The postnatal population of dermal macrophages is achieved by the infiltration of circulating monocytes given proper CCR2 signalling, a pathway responding to chemokines.[5][2][7] The infiltration of circulating monocytes can also be triggered through the upregulation of pro-inflammatory cytokines and chemicals such as sodium chloride.[1]
The infiltration of bone-marrow-derived monocytes generated postnatally creates a distinct population of dermal macrophages. They are
Function
Innate immunity
Dermal macrophages can phagocytose and digest foreign substances similar to other cell types in the mononuclear phagocyte system.[6] They construct the mononuclear phagocyte system together with dendritic and Langerhans cells.[5]
Dermal macrophages have a distinct expression of genes to facilitate their specialisation in removing macromolecules and foreign pathogens.[5] Therefore, they cannot infiltrate the lymph nodes because of their unique roles.[5] For instance, the cell population near postcapillary venules expresses CD4.[5] This specific population can produce chemokines to mediate the infiltration of neutrophils in an inflammatory response.[5] Dermal macrophages' functions suggest their importance in the skin’s innate immunity.
Dermal macrophages, Langerhans cells and dendritic cells are the main types of antigen-presenting cells (APCs) in the skin. However, dermal macrophages have a relatively lower influence on antigen-presenting than other APCs. Thus, dermal macrophages mainly serve as phagocytes in removing foreign substances.[5]
Wound repair
Dermal macrophages are primarily populated in the dermis of the skin as they are specialised in skin homeostasis and repair. There are three inter-linked stages in skin wound healing: inflammation, tissue formation, and maturation.[1][9] Dermal macrophages serve the function of bridging the three stages of wound healing.[9]
The first stage occurs from day 0 to 5 post-injury. This stage is an inflammatory response induced by dermal macrophages to initiate the tissue repairing process.
Tissue formation occurs from day 5 to 10 post-injury. In this stage, dermal macrophages' primary role is to generate a primary structure for wound repairing via granulation and collagen deposition.
Dermal macrophages mediate the final stage of
Hair growth
Dermal macrophages are the essential component of the hair follicle immune system.
In rodents, perifollicular macrophages can actively remove collagen fibres around the follicles via phagocytosis.[2] This phenomenon might contribute to remodelling the follicular composition during anagen when dermal macrophages prevent the activation of follicular stem cells, thereby preventing entry to catagen, a process in which hair stops growing. Hence, dermal macrophages facilitate the growth of the hair by preventing the halt of the growth process and its regression.[2]
When under physical stress, the release of
Dermal macrophages could also contribute to hair regeneration by skewing towards the anti-inflammatory phenotype (M2) under minor stress.[2] However, M2 dermal macrophages might also arrest the hair growth cycle at telogen.[1][2] Further research is needed to determine the functional roles of M2 dermal macrophages. Although the contribution of M1 and M2 dermal macrophages to hair regeneration is still unclear, the contribution of the dermal macrophage population is still noticeable regardless of their phenotypes.
Salt balance
Dermal macrophages facilitate skin homeostasis by regulating the skin's salt composition. For instance, an increase in salt concentration after a salt-heavy meal attracts dermal macrophages that express
A salt solution such as sodium chloride in the skin can trigger
Cancer resistance
Dermal macrophages can adjust their phenotypes to increase or suppress skin inflammation by different gene profiles, which can slow down the development of certain cancers. For instance, they can suppress the development of basal cell carcinoma.[1] Basal cell carcinoma is induced by mutations in PTCH1, a tumour-suppressor protein, leading to uncontrollable cell growth. In rodents, there is increased growth of basal cell carcinoma and loss of normal cells without the presence of macrophages.[1] Therefore, dermal macrophages are associated with cancer defence.
Interaction with other cells
The phenotypes of dermal macrophages can be affected by the cytokines expressed by other immune cells. They can obtain a pro-inflammatory (M1) or anti-inflammatory (M2) phenotype. Cytokines such as
Activation of dermal macrophages can also be achieved by direct contact. Ligands such as CD4 on T cells can trigger dermal macrophages to release pro-inflammatory cytokines during inflammation.[6] This process also preserves the population of circulating monocytes and thereby increases their activity.
Dermal macrophages are involved in the
Clinical significance
Psoriasis
Pro-inflammatory (M1) macrophages are responsible for the progression of psoriasis. They are mainly derived from infiltrated monocytes. M1 macrophages’ population could be as high as 60% of all the infiltrated immune cells during the disease onset.[4] They are the primary source of TNF-a, which leads to lesion development when there is a prolonged production of
TNF-a. TNF-a could also trigger M1 polarisation, which leads to further exaggeration of the disease. M1 macrophage ablation via adalimumab administration could alleviate psoriasis.[4]
Melanoma
Tumour-associated macrophages can be attracted by cytokines such as TGF-β and IL-10 produced by tumours in melanoma.[4] These cytokines can also trigger the M2 polarisation of the infiltrated tumour-associated macrophages. Infiltrated macrophages that acquire the M2 phenotype are anti-inflammatory. They facilitate tumour growth and proliferation via immunosuppression, further cytokine production, and tumour angiogenesis.[4] Tumour-associated macrophages also promote the invasion of cancer cells via the production of miRNA exosomes.[4]
Diabetes and obesity
Lacking anti-inflammatory dermal macrophages in diabetic patients results in impaired wound healing ability. Dermal macrophages are arrested at the pro-inflammatory phenotype, which increases the difficulty in the healing process due to their production of pro-inflammatory cytokines.[4] Ulcers on foot are common in a patient with severe diabetes due to the prolonged impairment of wound healing.[4]
Pro-inflammatory (M1) macrophages are also frequently observed in obese individuals' subcutaneous tissues. This is related to the progression of diabetes with chronic adipose tissue inflammation.[4] However, the explicit roles of dermal macrophages in obesity are still unclear.
See also
- Skin
- Hair follicle
- Macrophage
- Dendritic cell
- Langerhans cell
- Macrophage polarisation
- Inflammation
- Phenotypes of macrophages
- Phagocytosis
- Angiogenesis
- Melanoma
- Basal cell carcinoma