2015 ACR/ARHP Annual Meeting: Immune Mediators Can Impact Inflammatory Response

“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.