Iain Fraser, Ph.D.

Behind almost every chronic disease affecting Americans today, from heart disease and obesity to Alzheimer’s and cancer, lies a common theme; unchecked inflammation. While inflammation is a critical and necessary bodily response to injury or infection, it must be tightly regulated and properly resolved after healing. When the body’s control of the inflammation cycle breaks down, it can slip into a state of low level ‘chronic’ inflammation, where a once protective mechanism becomes a silent, ongoing threat to long-term health. Over time, and often without noticeable symptoms, this chronic inflammation will lead to development of one or more of the chronic diseases mentioned above.

There are two primary strategies to combat these chronic inflammatory diseases; 1) prevent the onset of low-level chronic inflammation in the first place, or 2) reverse the inflammatory state in individuals with ongoing chronic disease. To develop effective treatments and therapies in each of these two areas, we must deepen our understanding of the mechanisms in the cell that drive inflammation.

When it comes to examining inflammation, the most important cell in the human body is the macrophage. Macrophages take on many forms in every tissue of the body and their primary role is surveillance. They patrol the tissues of our body as the immune systems’ first line of defense, constantly looking for signs of infection or injury. These signals can come from microbes, such as bacteria, viruses or parasites, or from the body’s own damaged cells, which release biochemical cues (‘danger’ signals) when injury occurs. In both cases, macrophages recognize the signals using pattern recognition receptors (PRRs), proteins in the cell that recognize and alert the body to specific molecular patterns associated with infection or injury.

Our laboratory studies the cellular signaling systems in macrophages that are activated through PRRs to drive inflammation. The two primary systems we study are toll-like receptor (TLR) pathways, and NOD-like receptor (NLR) pathways. The TLR pathways are the primary pathways for responding to microbial infection, although they can also be activated by tissue injury. In contrast, the NLR pathways activate the so-called ‘inflammasome’, a major complex of inflammatory factors that mediate the response to cellular stress. Once activated, both pathways prompt the release of inflammatory mediators known as cytokines. Among these, tumor necrosis factor (TNF) and interleukin-1 (IL-1) family cytokines play a particularly critical role in driving disease. The importance of these specific cytokines in inflammatory disease is evidenced by the enormous success of anti-inflammatory drugs and biologics which block TNF and IL-1 activity.

Our research program is focused on the design, implementation, and interpretation of screening efforts to identify and determine the interactions among the components in PRR signaling systems. We use high-throughput genetic screening to identify key pathway regulators, and a combination of cell biology, biochemistry, and molecular biology to characterize their function. An additional focus is on the mechanisms of trained immunity, which can establish innate immune memory in macrophages. We have used high-throughput chemical screens to identify novel training molecules, and are exploring the therapeutic potential of such molecules in treating chronic infections. We believe that the described screening and therapeutic validation of novel drug candidates will help us tackle the ongoing challenges of chronic inflammatory disease.