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Inflammation, a process that involves every cell in the body, has evolved over millions of years to protect us from infection and help heal wounds. However, the detrimental effects of excessive inflammation are a core component of nearly every disease process. Although inflammation is a critical part of defending our bodies from pathogens, physicians and scientists now understand that it represents a complex system. When inflammation spirals out of control, the ensuing storm of cytokines and other inflammatory mediators can quickly cause organ dysfunction and death. We are just scratching the surface of how we might wisely intervene for the betterment of disease.
As part of the Richard King Mellon Institute for Pediatric Research, the research team led by pediatric rheumatologist Scott Canna, MD, is studying the mechanisms that drive disorders of excessive inflammation. This includes autoinflammatory diseases like periodic fever syndromes and systemic juvenile idiopathic arthritis, as well as hyperinflammatory cytokine storm syndromes like macrophage activation syndrome (MAS) and hemophagocytic lymphohistiocytosis (HLH).
Dr. Canna’s team leverages insights from the clinic, detailed genetic and immunologic testing, biomarker discovery, and various model systems to understand the mechanisms underlying uncontrolled systemic and organ-specific inflammation. Its ultimate aim is to translate these insights into better diagnostic and therapeutic options for patients.
With a better understanding of the causes of inflammation in systemic inflammatory response syndrome (SIRS), the Canna Lab hopes to make diagnosis more timely and precise, and most importantly, find ways to therapeutically temper the inflammatory response.
Inflammation originates from many sources, such as infection, trauma, allergy, autoimmunity and more. It manifests in a dizzying array of varieties and combinations that change over time and with treatment. With such complexity, finding solid places to start investigating is challenging. The revolution in high-throughput sequencing has resulted in the identification of an increasing number of monogenic (single-gene) defects associated with excessive inflammation.
Members of the Canna Lab team are currently focused on these subject areas: Defining subsets of sepsis; Abnormal activation of the inflammasome; and IL-18 and macrophage activation syndrome.
A schematic of the mechanisms resulting in systemic macrophage activation. In familial hemophagocytic lymphohistiocytosis (a), cytotoxic lymphocytes lack the ability to kill infected antigen-presenting cells. In macrophage activation syndrome (b), intrinsic defects such as hyperactivity of the NLRC4 inflammasome could prime for macrophage activation directly but could also lead to other outcomes, including cell death.
Millions of dollars and decades spent studying the inflammatory underpinnings of sepsis have reinforced the difficulty of addressing the “I” in SIRS, or systemic inflammatory response syndrome. Our research team is interested in both learning from and modeling how biomarkers can define the type and degree of inflammation in SIRS. Such knowledge will hopefully equip us with the information we need to make informed immunologic interventions.
In particular, a subset of septic patients has physiologic characteristics akin to macrophage activation syndrome (MAS). Through internal and extramural collaborations and careful model system interrogation, we will better define the borders of this sepsis/MAS overlap and hopefully define other kinds of sepsis amenable to immunologic treatment.
Heat map of serum cytokines comparing individuals with NLRC4 and NLRP3-related inflammasome hyperactivity identified a cytokine signature anchored by IL-18.
The inflammasome is a potentially massive complex of proteins that assembles in response to a variety of intracellular danger signals. Once activated, inflammasomes catalyze the activation of the inflammatory cytokines IL-1β and IL-18, and they activate a cell death pathway called pyroptosis through the activation of a pore-forming protein called gasdermin D (GSDMD).
Inflammasomes are best studied in macrophages, but they are active in many other immune and non-immune cells. Likewise, IL-1β, IL-18, and pyroptosis are important in many different kinds of inflammatory responses.
Mutations in several proteins known to “nucleate” an inflammasome have been associated with autoinflammatory diseases. Foremost among these are MEFV, the gene associated with familial Mediterranean fever; NLRP3, the gene associated with neonatal onset multisystem inflammatory disease; and NLRC4, a gene associated with macrophage activation syndrome. Although mutations in any of these genes can cause increased inflammasome activation, the diseases are distinct.
This begs the question as to what makes these inflammasomes different. Our research team aims to leverage patient samples and various model systems to find out.
Spontaneous aggregation of ASC as a readout for inflammasome formation in an individual with NLRC4-associated macrophage activation syndrome.
Macrophage activation syndrome (MAS) is a type of systemic inflammatory response syndrome distinguished by high fever, cytopenias (low cell counts), liver dysfunction, clotting problems, extremely high levels of ferritin, and often hemophagocytosis (macrophages that have consumed other blood cells). Though rheumatologists grapple with MAS as a complication of some rheumatic diseases, MAS-like physiology is seen in other contexts, such as viral and bacterial infection, cancer and transplantation.
One feature that seems to define MAS is extraordinary elevation of the cytokine Interleukin-18 (IL-18). IL-18 requires an inflammasome for its activation, but until recently it was unclear whether IL-18 was helping drive MAS or was just an epiphenomenon. We recently discovered an association between the NLRC4 inflammasome, extraordinary IL-18, and MAS. We are actively working to fill in the mechanistic gaps.
A murine splenic hemophagocyte.
Increased proliferation of intestinal epithelial cells in NLRC4 gain-of-function mice.
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Kathryn C. (KC) Little, MA, RN, CCRC
Research Nurse Coordinator
Research Technician/Lab Manager
Paul A. Tsoukas, MD
Pediatric Rheumatology Fellow
Eric S. Weiss
The Canna Lab
UPMC Children’s Hospital of Pittsburgh
John G. Rangos Sr. Research Center, Suite 8124
4401 Penn Avenue
Pittsburgh, PA 15224
Navigating the Cytokine Storm, a podcast featuring Scott Canna, MD, was added to the “That’s Pediatrics” series.
The Canna Lab is seeking talented, curious and driven graduate students and post-doctoral and clinical fellows, who are interested in understanding the relevant mechanisms that drive hyper- and autoinflammation. Please contact Dr. Canna via email to discuss opportunities within our team.
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