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SAN FRANCISCO—Inflammation can be either acute or chronic, and it’s the inflammatory responses that don’t shut down normally, or resolve, that cause tissue damage in rheumatic disease.
“Resolution bridges the gap between acute inflammation and adaptive immunity,” said Derek W. Gilroy, PhD, head of the Centre for Clinical Pharmacology and Professor of Immunology at University College, London.
Which way the inflammatory process turns at key intervals can depend on certain immune mediators, said a panel of speakers at the at the 2015 ACR/ARHP Annual Meeting on Nov. 7. These mediating factors include fatty acids, such as fish oil in the diet, phagocytes like macrophages that may help clean house after infection or trauma, and various inflammasomes that can trigger a chronic response. Although acute inflammation should go through a quick process to resolution, that’s not always the end of the story. How these mediators behave may tell us more about why some patients’ inflammation turns chronic.
Fish Stories
Omega-3 fatty acids in such foods as fish have been a focus of interest for years as a possible way to influence inflammation through diet or supplementation, said Leslie G. Cleland, MD, FRACP, director of rheumatology at Royal Adelaide Hospital in Australia.
“What messages do we convey to people about dietary, unsaturated fatty acids?” said Dr. Cleland. Omega-3s, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), balance the omega-6 fatty acids found in seed oils used in many processed foods. The omega-6 fatty acids are remodeled to form eicosanoids, which amplify inflammatory responses. EPA and DHA compete for enzymes involved in eicosanoid formation, and tend to reduce the intensity of inflammation. Due to these effects, could adding fish to the diet or taking fish oil supplements play a part in treat-to-target management of rheumatoid arthritis?
Dr. Cleland
“Taking fish oil, while reducing omega-6 fats, is the least expensive and most reliable way to increase n-3, long-chain, polyunsaturated fatty acids in tissues,” he said. Omega-6 fats lead to the production of arachidonic acid, which then triggers prostaglandin production. But dietary omega-3 fats like EPA and DHA are competitive inhibitors of omega-6, and help suppress inflammatory cytokines like IL-1 and TNFα in joint synovial tissue, Dr. Cleland said.
In a long-term study of fish oil as a complementary therapy published in the Annals of the Rheumatic Diseases in 2013, Dr. Cleland and his colleagues looked at how adding a daily supplement of DHA and EPA, along with triple disease-modifying anti-rheumatic drug (DMARD) therapy of methotrexate, sulfasalazine, and hydroxychloroquine, helped improve disease activity scores in patients with early RA.1 Patients who received 5.5 g of fish oil, compared with controls who received only 0.4 g of fish oil, had lower rates of triple DMARD failure therapy and higher rates of ACR remission. The patients in both groups reported similar rates of DAS28 scores and adverse events, Dr. Cleland noted.
Earlier studies of the Inuit living in Arctic regions provided evidence that people consuming a diet dominated by omega-3 fats had vastly lower rates of myocardial infarction compared to people living in developed countries.2 They also had a lower frequency of autoimmune and inflammatory diseases, yet as much as a 60% higher rate of apoplexy, Dr. Cleland said.
‘Why should we be interested in acute inflammation & its resolution in the realm of a chronic disease like RA?’ —Derek W. Gilroy, PhD
“The diet of the Inuit in their aboriginal state consists of sea mammals, fish and sea birds. The omega-3 fatty acids found in these marine vertebrates have their origins in the sea algae that these animals eat,” he said. Although an omega-3-rich diet can positively affect serum lipids, cholesterol and high blood pressure, key drivers of cardiovascular disease, “as for anti-thrombosis, the effect of omega-3 fats is relatively modest.”
In a 2011 study published in Cardiology, people given fish oil after coronary artery bypass grafting surgery did not have statistically significant delayed time of onset to atrial fibrillation, an irregular heartbeat that can raise stroke risk, but did spend significantly less time in the intensive care unit after surgery, he said.
Fish oil’s potential benefits as an inflammatory mediator could be jeopardized by the sustainability of the world’s fish supply, so metabolic engineering of plant seeds, such as rapeseed, to achieve levels of DHA similar to fish oil, may help fill the need, said Dr. Cleland. “Fish oil has a place in the treat-to-target management of RA, and GMO crops may have a future role.”
Road to Resolution
After an acute infection or injury, inflammation kicks in for a quick immune response. Polymorphonuclear cells like neutrophils and eosinophils migrate to affected tissue within hours to attack bacteria. A clean-up crew of macrophages then move in to sweep out whatever is left, preparing the tissue for homeostasis and resolution.
“Why should we be interested in acute inflammation and its resolution in the realm of a chronic disease like RA?” said Dr. Gilroy. Understanding how mediators behave in self-limiting inflammation may tell us more about what may go wrong in other situations.
Resolution is not the final chapter of acute inflammation, and resolution of inflammation amplifies adaptive immunity, he said. In a 2014 study published in Blood, mice were infected to cause peritonitis and then treated with 10 g of zymosan.3 Dr. Gilroy and his fellow researchers found that even after resolution of the inflammation within 72 hours, a second wave of leukocytes entered the peritoneal cavity and persisted for weeks. Tissues do not revert back to the state they were before inflammation, but instead are in a state of adapted homeostasis, which may intensify future inflammatory responses, he said.
“We began to think of inflammation as having three stages: onset, resolution and post-resolution,” he added. In the post-resolution phase, various macrophages, B cells and T cells can be present. To get to resolution, neutrophils and eosinophils must be disposed of in a controlled, effective manner, ideally through apoptosis and phagocytosis.
Chronic inflammation in diseases like RA may be a case of frustrated resolution, he said. That post-resolution phase may be a change from innate to adaptive immunity, and tissue reprogramming instead of restored equilibrium.
Dysregulated Response
Adaptive immunity usually is initiated when there is a dysregulated inflammatory response, said Karsten Gronert, PhD, professor and chair of the Vision Science Program at the University of California at Berkeley.
Well-known lipid circuits help regulate successful resolution of inflammation, he said. Therapeutic targets for inflammatory rheumatic diseases and RA include the lipid mediators leukotriene B4, prostaglandin E2 (PGE2) and lipoxin A4.
Dr. Gronert
Innate immunity triggers an inflammatory response to pathogens. “A healthy body contains more bacteria than cells. How can the body distinguish between healthy bacteria and pathogenic threats?” said Dr. Gronert. Pathogen-associated molecular patterns, recognized by the innate immune system through Toll-like receptors, can activate the immune response, but they don’t necessarily tell good from bad pathogens.
Failure to detect a pathogen leads to unchecked pathogen replication. If the innate immune system responds with inflammation when there is no pathogen present, it can result in inflammatory disease followed by autoimmune pathology, Dr. Gronert said.
Inflammasomes are cytosolic censors that help the body detect infectious and pathogenic invaders. Inflammasomes activate CASPASE-1 protease, which triggers pyroptosis, a type of programmed cell death, in a few hours, and then promotes the release of the inflammatory cytokines IL-1ß and IL-18 within 12 to 24 hours.
In a 2012 study published in Nature, infection by a fusion of Legionella pneumophila flagellin and Bacillus anthracis (called FlaTox) activated a systemic inflammasome response that triggered a rapid “eicosanoid storm” in mice.4 Within 28 minutes, the mice died due to massive fluid loss and plummeting body temperatures. Mice with the inflammasome Nlrc4/Naip5 knocked out were protected from FlaTox-induced vascular leakage and death. The eicosanoid storm, which caused the deadly reaction, is a novel and early effector function of inflammasomes, Dr. Gronert said.
Resident peritoneal macrophages were identified as the specific source of that eicosanoid storm. These macrophages highly express the prostaglandin biosynthetic enzymes cyclooxygenase-1 (COX-1), 5-lipoxygenase, and 15-lipoxygenase. When activated, they generate an eicosanoid storm that includes immune-regulating and vaso-regulating PGE2. Only animals that are deficient in or have deleted COX-1 are protected from the effects of that inflammasome activation, Dr. Gronert said.
PGE2 and eicosanoids are a previously unrecognized resident macrophage-specific source of inflammasome activation. When this eicosanoid response is dysregulated, it has severe consequences, and it’s a likely factor in innate immunity-driven diseases, Dr. Gronert said.
Susan Bernstein is a freelance medical journalist based in Atlanta.
References
- Proudman SM, James MJ, Spargo LD, et al. Fish oil in recent onset rheumatoid arthritis: A randomised, double-blind, controlled trial within algorithm-based drug use. Ann Rheum Dis. 2015 Jan;74(1):89–95. doi: 10.1136/annrheumdis-2013-204145. Epub 2013 Sep 30.
- Bjerregaard P, Young TK, Hegele RA. Low evidence of cardiovascular disease among the Inuit—What is the evidence? Atherosclerosis. 2003 Feb;166(2):351–357.
- Newson J, Stables M, Karra E, et al. Resolution of acute inflammation bridges the gap between innate and adaptive immunity. Blood. 11 Sep 2014;124(11):1748–1764. doi: 10.1182/blood-2014-03-562710. Epub 2014 Jul 8.
- Von Moltke J, Trinidad NJ, Moayeri M, et al. Rapid induction of inflammatory lipid mediators by the inflammasome in vivo. Nature. 2012 Oct 4;490(7418):107–111. doi: 10.1038/nature11351. Epub 2012 Aug 19.
