Activation of α7 Nicotinic Acetylcholine Receptor Decreases On-site Mortality in Crush Syndrome through Insulin Signaling-Na/K-ATPase Pathway

Intermittent intense ultraviolet (UV) exposure represents an important aetiological factor in the development of malignant melanoma. The ability of UV radiation to cause tumour-initiating DNA mutations in melanocytes is now firmly established, but how the microenvironmental effects of UV radiation influence melanoma pathogenesis is not fully understood. Here we report that repetitive UV exposure of primary cutaneous melanomas in a genetically engineered mouse model promotes metastatic progression, independent of its tumour-initiating effects. UV irradiation enhanced the expansion of tumour cells along abluminal blood vessel surfaces and increased the number of lung metastases. This effect depended on the recruitment and activation of neutrophils, initiated by the release of high mobility group box 1 (HMGB1) from UV-damaged epidermal keratinocytes and driven by Toll-like receptor 4 (TLR4). The UV-induced neutrophilic inflammatory response stimulated angiogenesis and promoted the ability of melanoma cells to migrate towards endothelial cells and use selective motility cues on their surfaces. Our results not only reveal how UV irradiation of epidermal keratinocytes is sensed by the innate immune system, but also show that the resulting inflammatory response catalyses reciprocal melanoma-endothelial cell interactions leading to perivascular invasion, a phenomenon originally described as angiotropism in human melanomas by histopathologists. Angiotropism represents a hitherto underappreciated mechanism of metastasis that also increases the likelihood of intravasation and haematogenous dissemination. Consistent with our findings, ulcerated primary human melanomas with abundant neutrophils and reactive angiogenesis frequently show angiotropism and a high risk for metastases. Our work indicates that targeting the inflammation-induced phenotypic plasticity of melanoma cells and their association with endothelial cells represent rational strategies to specifically interfere with metastatic progression.

Immune responses are initiated and perpetuated by molecules derived from microorganisms pathogen-associated molecular-pattern molecules or from the damage or death of host cells [damage-associated molecular-pattern (DAMP) molecules]. Many DAMPs are nuclear or cytosolic proteins with defined intracellular function that, when released outside the cell following tissue injury, move from a reducing to an oxidizing milieu resulting in their functional denaturation. Here, we discuss the consequences of DAMP oxidation on the outcome of acute inflammation. We also suggest that, outside the cell, DAMPs might adopt novel conformations or alter the redox of the extracellular environment to more closely mimic the internal one, thereby avoiding oxidation-mediated inactivation and promoting pathology. We propose that chronic inflammation associated with autoimmunity, chronic viral infection and cancer is probably mediated by persistent release and function of DAMPs, promoting and promoted by a disordered redox environment.

Obesity is associated with a chronic inflammatory state characterized by adipose tissue macrophage infiltration and inflammation, which contributes to insulin resistance. The cholinergic antiinflammatory pathway, which acts through the macrophage α7-nicotinic acetylcholine receptor (α7nAChR), is important in innate immunity. Here we show that adipose tissue possesses a functional cholinergic signaling pathway. Activating this pathway by nicotine in genetically obese (db/db) and diet-induced obese mice significantly improves glucose homeostasis and insulin sensitivity without changes of body weight. This is associated with suppressed adipose tissue inflammation. In addition, macrophages from α7nAChR-/- [α7 knockout (α7KO)] mice have elevated proinflammatory cytokine production in response to free fatty acids and TNFα, known agents causing inflammation and insulin resistance. Nicotine significantly suppressed free fatty acid- and TNFα-induced cytokine production in wild type (WT), but not α7KO macrophages. These data suggest that α7nAChR is important in mediating the antiinflammatory effect of nicotine. Indeed, inactivating this pathway in α7KO mice results in significantly increased adipose tissue infiltration of classically activated M1 macrophages and inflammation in α7KO mice than their WT littermates. As a result, α7KO mice exhibit more severely impaired insulin sensitivity than WT mice without changes of body weight. These data suggest that the cholinergic antiinflammatory pathway plays an important role in obesity-induced inflammation and insulin resistance. Targeting this pathway may provide novel therapeutic benefits in the prevention and treatment of obesity-induced inflammation and insulin resistance.