Long-term activity of the IIS results in low-grade inflammation and chronic disease. Over the past years, ideas regarding the treatment of inflammation have started to change as evidence accumulates which shows that, although the targeting of infiltrating immune cells can control the inflammatory response, it does not lead to its complete resolution and a return to homeostasis, which is essential for healthy tissue and good health in general.
Hotamisligil describes how low-grade, chronic inflammation ('meta-inflammation') induced by a nutritional and metabolic surplus, is accompanied by disturbed metabolic pathways and chronic metabolic disorders. He states that this inflammatory response differs from the classical inflammation response caused by injury [117
]. However, others have shown that the classical response of the IIS dealing with injuries can be linked to activation of the central stress axes [26
]. This article specifically discusses the relationship between the over-activated systemic stress system and the self-limited process of inflammation, known as Resoleomics, executed and controlled by the innate immune system (IIS).
Changes in lifestyle which are new to our evolutionary process should be considered a major trigger in causing chronic activation of the IS and consequently of the central stress axes and vice versa, thereby leading to chronic diseases such as cardiovascular diseases (CVD), diabetes, respiratory diseases, mental disorders, auto-immune diseases (AID) and cancers. This article evaluates two of the lifestyle changes which contribute to long-term activity of the ISS, namely, nutrition and continuous psycho-emotional stress. Other risk factors such as physical inactivity [6
], genetic susceptibility [118
], smoking, environmental toxicity and shift work [119
] fall beyond the scope of this article but should not be ruled out.
Nutrition is an important factor in understanding the development of chronic inflammation. The current Western diet can disturb the resolution response in various ways (Figure ). In the Ancestral human diet, foodstuffs with an increased risk of inflammation were virtually unknown, while nutrients able to activate the IIS are now abundant in our diet [38
]. Cordain's research has focused on relating these anti-nutrients in food (eg lectines, saponines) to the development of chronic inflammation and autoimmune diseases (AID) [7
]. Fortunately, it seems that the human body possesses a strong capacity to recover from illness. If our genes are exposed to their 'original' environment by intake of an ancestral human diet, their function can recover rapidly. Research has shown that obese persons improve their blood markers after just 10 days following a paleolithic diet consisting of fish, lean meat, fruit, vegetables and nuts [121
]. Similar results have been found in a study with aboriginals suffering from Diabetes II, who showed normalized blood markers after returning to their traditional lifestyle for seven weeks [122
Reflection of the working mechanism demonstrating how several nutritional factors could induce and inhibit inflammation.
People suffering from chronic inflammatory disease demonstrate over-activated central stress axes, which then lead to catecholamines, cortisol and insulin resistance. McGowan et al [123
] show the impact of childhood abuse on the epigenetic pattern of different genes including the gene for GR in the hippocampus. They found a decreased level of GR and an increased methylation pattern of the GR gene, giving rise to a situation of lower cortisol sensibility and altered HPA stress responses. This could make people more vulnerable to developing diseases. An altered sensitivity to cortisol has been linked to diseases such as rheumatoid arthritis (RA) [124
], post-traumatic stress syndrome [125
], chronic fatigue syndrome [126
], inflammatory diseases and AID in general [127
The key priority in the treatment of people with chronic inflammation is to induce the Eicosanoid Switch to the anti-inflammatory resolution phase. Long-lasting cortisol resistance and insulin resistance will definitely delay or block complete resolution. The combination of local factors (ie DHA deficiency, low levels of protectins) disturbing the process of complete resolution (ie Resoleomics) and the absence of adequate NE and cortisol signalling can be responsible for perpetuatual inflammation by delaying the resolution phase of the inflammatory response (Figure ).
Figure 7 Chronic over-activation of the systemic stress system as a result of external stressors plays a central role in the development of chronic inflammatory diseases. Current intervention with anti-inflammatory medication suppresses Resoleomics and the IIS (more ...)
Current anti-inflammatory medication used in RA treatment is aimed at the suppression of the IIS and its inflammatory response and thus hinders Resoleomics. In addition, these medication interventions do not solve underlying catecholamine, cortisol and insulin resistance, and consequently making it impossible to achieve full recovery of the chronic inflammation. This suggests that chronic use of anti-inflammatory medication in fact impedes the body from making a full recovery. Furthermore, the ongoing low-grade inflammation will continuously trigger the activity of the systemic stress system [28
Health care should focus on early detection of silent, ongoing and low-grade inflammation in order to avoid the development of many chronic diseases. Further research is needed to validate a questionnaire which addresses early symptoms of chronic low-grade inflammation, ie avoidance of exercise, fatigue, emotional flatness, social isolation, decreased libido, hyper or hyposomnia, obsessive behaviour or sensitivity to addiction [6
We have made an effort to demonstrate that the science of Resoleomics can help to find new ways to treat people suffering from diseases based on chronic inflammation. Since over-activated central stress axes directly delay Resoleomics, and thereby delay the resolution of inflammation, treatment should focus on restoring the central stress system to its default, healthy homeostasis. Dietary changes, psycho-emotional stress release and physical activity should always be included in treatment of all chronic inflammatory diseases.