Inflammation occurs when one of the pathways discussed below is activated. It is a complicated process because all of the pathways influence each other on, causing a domino effect. This is a brief discussion of the science of what causes skin inflammation.
This material is adapted from Anti-inflammatory Ingredients in Ch. 38 of Baumann’s Cosmetic Dermatology (McGraw Hill 2022)
Eicosanoids in Skin Inflammation
Phospholipids found in the cell membrane are hydrolyzed by phospholipase A2 (PLA2), releasing free arachidonic acid (AA). This fatty acid is the primary precursor of eicosanoids. Eicosanoids are mediators of inflammation. Types of eicosanoids are:
There are two different pathways in the synthesis of eicosanoids from AA:
- Cyclooxygenase (COX) pathway: Prostaglandins, thromboxanes, and prostacyclins
are synthesized via the cyclooxygenase pathway. Two cyclooxygenases have been identified: COX-1 and COX-2. COX-1 is ubiquitous. COX- 2 is induced in response to inflammatory stimuli.
- Lipoxygenase pathway: Lipoxygenase enzymes can act on AA to form hydroperoxyeicosatetraenoic (HPETE) acids (5-HPETE, 12-HPETE, and 15-HPETE). HPETEs are then rapidly reduced to hydroxylated derivatives (HETEs), LTs, or lipoxins.
Cytokines in Skin Inflammation
Cytokines are signals that cells produce. Cytokines that play a role in inflammation are produced by various cell types, but the most important sources are the immune cells: macrophages and monocytes found in the inflammatory areas. See Table “Inflammation-Associated Cytokines” so see which cytokines play a major role in inflammation.
As seen in the table, numerous types of cytokines play a role in skin inflammation. Two of these orchestrate inflammation: interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α). These two cytokines induce the production of lipid mediators, proteases, and free radicals. The cytokines interferon-γ (INF-γ) and granulocyte colony-stimulating factor (G-CSF) amplify the inflammatory response by increasing the production of IL-1 and TNF-α by macrophages.
Chemokines (chemotactic cytokines) are small proteins that direct the movement of circulating white blood cells to areas of inflamed skin.
Mast Cells in Skin Inflammation
Mast cells are activated to release histamine by binding the immunoglobulin E (IgE) or by physical stimuli (e.g., heat, cold, and sunlight), macrophage-derived cytokines, bacterial toxins, venoms, trauma, and the presence of allergens.
When a mast cell armed with IgE antibodies is re-exposed to an allergen, multiple responses occur, leading eventually to the release of various potent mediators responsible for the clinical expression of immediate inflammatory-hypersensitivity reactions that is commonly called “an allergic reaction” or “hives”. In the first step of this sequence, antigens bind to the IgE antibodies previously attached to the mast cells. The bridging of IgE molecules with the underlying IgE-Fc receptors activates signal transduction pathways that will translate into three outcomes:
1) Degranulation, with the secretion of preformed mediators like vasoactive amines (e.g., histamine), neutral proteases (e.g., chymase, tryptase, hydrolase), and proteoglycans (e.g., heparin, chondroitin sulfate);
2) De novo synthesis of pro-inflammatory lipid mediators (i.e., LTs C4, D4, and B4, and PG D2)
3) Synthesis and secretion of cytokines (i.e., TNF-α, IL-1, IL-3, IL-4, IL-5, IL-6, and GM-CSF), as well as chemokines, such as macrophage inflammatory protein (MIP)-1α and MIP-1β.
Histamine and Skin Inflammation
Histamine is stored in mast cells. When mast cells degranulate, they release histamine. When histamine binds the H1-receptor, cytokines and lysosomal enzymes from macrophages are released and cell-adhesion molecules are expressed which influences the activity of basophils, eosinophils, and fibroblasts. Both the H1- and H3-receptors play a role in the itching felt during a skin allergy.
Free Radicals and Skin Inflammation
White blood cells release oxygen-derived free radicals after exposure to challenges such as microbes, chemokines, or immune complexes. Free radicals cause the expression of chemokines, cytokines, and endothelial leukocyte adhesion molecules, amplifying the inflammatory cascade and making inflammation worse. High levels of free radical cause cell damage triggering more inflammation and destruction of the extracellular matrix and loss of hyaluronic acid, collagen, and elastin.
Kinins in Skin Inflammation
The kinin-kallikrein system is a network of circulating proteins that affect inflammation, blood pressure control, coagulation, and pain. Kinins [bradykinin (BK) and kallidin (KD)] are polypeptides produced from kininogen and broken down by kininases. They are rapidly generated after tissue injury and they affect the inflammatory process by increasing arachidonic acid release and increasing eicosanoid production and activating nuclear factor-κB (NF-κB), further contributing to the inflammatory response. Kinins also induce pain.