Inflammatory Pathways Modified By Smoking in Psoriasis
Histological hallmarks of psoriasis include keratinocyte hyperproliferation (acanthosis), immature cells in the stratum corneum (parakeratosis), a subepidermal inflammatory cell infiltrate, and permeable dermal neovessels. A complex inflammatory cascade leads to the development of this phenotype, beginning with the activation of innate immune cells. In response to an environmental insult, macrophages, natural killer T cells (NKC), plasmacytoid DCs and keratinocytes produce cytokines such as tumour necrosis factor (TNF)-α, interferon (IFN)-α, IFN-γ, interleukin (IL)-1β and IL-6 that activate myeloid DCs to secrete IL-12 and IL-23. IL-12 triggers the differentiation of type 1 helper T cells, which then secrete mediators including IFN-γ and TNF-α, which in turn stimulate the innate cells further and perpetuate a cycle of chronic inflammation. Smoking has been shown to activate a number of these immune cell processes.
Smoking-induced Immune Cell Activation in Psoriasis
Nicotine – in concentrations similar to those found in the blood of active, chronic smokers – binds to nicotinic acetylcholine receptors (nAChRs) on DCs, inducing a significant increase in IL-12 secretion and expression of the maturation marker CD83, adhesion molecules lymphocyte function-associated antigen-1 and intercellular adhesion molecule-1 (ICAM-1), major histocompatibility complex (MHC) class II molecule HLA-DR, and costimulatory molecules CD86 and CD40 (Fig. 2). These features allow DCs to stimulate T cells more effectively. When ligated, CD40 induces further secretion of IL-12. Nicotine-stimulated DCs promote CD40 ligand (CD40L) and IL-2 production by T lymphocytes. IL-2 stimulates the activity and proliferation of cytotoxic T cells, NKC, monocytes, macrophages and haematopoietic stem cells. IL-2 can trigger production of IFN-γ, TNF, IL-6, granulocyte/macrophage colony-stimulating factor, as well as more IL-2. CD40L is overexpressed in early psoriatic lesions. Notably, elevated blood levels of CD40L also predict an increased risk of adverse cardiovascular events, including death.[50–51]
Nicotine-stimulated pathways involved in the development of psoriasis. Nicotine (N) binds to nicotinic acetylcholine receptors (nAChRs) on dendritic cells (DCs), macrophages, endothelial cells (ECs) and keratinocytes. This leads to inflammation via Th1 and innate immune cell stimulation, enhanced leucocyte migration through increased expression of intercellular adhesion molecule-1 (I) and vascular cell adhesion molecule-1 (V), pathological angiogenesis, and keratinocyte proliferation. IL, interleukin; 1β, IL-1β; IFN, interferon; NKC, natural killer T cells.
In addition to indirect stimulation via IL-2, nicotine directly stimulates macrophages to produce IL-1β and TNF-α, which then induce expression of ICAM-1 and vascular cell adhesion molecule-1 on endothelial cells. This causes increased leucocyte adhesion to capillary walls, enabling inflammatory cells to infiltrate the dermis. This mechanism is likely to be important in psoriasis pathogenesis, as mice lacking IL-1β receptor antagonist have been shown to develop psoriasiform dermatitis, arthritis and arteritis spontaneously. Smokers also demonstrate enhanced neutrophil chemotaxis,[54–55] which further promotes formation of a dermal infiltrate.
With regard to keratinocytes, smoking may be an environmental trigger capable of inciting not only innate immune function, but also other characteristic changes. In a series of studies, Grando et al. demonstrated that nAChR stimulation significantly increased keratinocyte mitosis, migration, differentiation and adhesion.56–58 With repeated stimulation of the receptor by nicotine, these cellular processes could lead to acanthosis and formation of the characteristic epidermal psoriasis plaque.
Smoking-induced Pathological Angiogenesis in Psoriasis
Dermal microvascular changes precede the clinical appearance of psoriasis plaques and provide conduits for inflammatory cell infiltration of the skin.[59–60] A key player in this pathological angiogenesis is vascular endothelial growth factor (VEGF).[61–64] In fact, VEGF overexpression in transgenic mice can induce not only characteristic microvascular changes, but the entire psoriasiform phenotype. Serum VEGF levels have been shown to be elevated in male smokers compared with male nonsmokers. While some evidence suggests that smoking impairs vascular repair mechanisms, other experiments show that nicotine binding to the nAChR promotes endothelial cell network formation and capillary growth to the same extent as VEGF. Heeschen et al. also noted that this nicotine-induced increase in neovascularization was associated with a significant acceleration in atherosclerotic plaque growth compared with control mice. Stimulation of pathological angiogenesis may be a key mechanism by which smoking promotes both psoriasis and atherosclerotic diseases.
Tobacco smoke contains thousands of chemicals, several dozen of which are known carcinogens. While certain components of cigarette smoke promote inflammatory events involved in psoriasis pathogenesis, others are toxic to immune cells. Nicotine has been shown to deplete the calcium stores of T lymphocytes, probably impairing their function. Similarly, stimulation of the nAChR α7 subtype led to decreased T-cell proliferation. However, deficiency of this nicotinic receptor hampered the activity of antigen-presenting cells. The net effect of pro- vs. anti-inflammatory influences exerted by tobacco smoke probably influences whether or not smoking induces psoriasis in a given individual.
The British Journal of Dermatology. 2011;165(6):1162-1168. © 2011 Blackwell Publishing