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Chronic Inflammatory Disease

By: Gayle Joseph Date: Mar 19, 2020
Dr. Elizabeth Lennon in her laboratory, which is funded by the National Institutes of Health/Office of Research Infrastructure Programs (K01 OD019729 and R03 OD026599).
Dr. Elizabeth Lennon in her laboratory, which is funded by the National Institutes of Health/Office of Research Infrastructure Programs
(K01 OD019729 and R03 OD026599).

Inflammatory bowel disease (IBD) affects more than three million people in the United States. The research of Dr. Elizabeth Lennon, Pamela Cole Assistant Professor of Internal Medicine  in the Department of Clinical Sciences and Advanced Medicine, focuses on immunoregulatory roles of mast cells in inflammatory diseases, particularly in IBD.

IBD is a debilitating, incurable disease; patients are frequently hospitalized and require lifelong treatment with immunosuppressive medications. Despite medical therapy, affected individuals can also develop fibrosis, resulting in intestinal strictures that often require surgical treatment.

The disease is thought to result from a complex interaction between genetic predisposition, environmental factors, an altered intestinal microbiome, and immune dysregulation. Over the last 10 years, the importance of the innate immune system in the pathogenesis of IBD has become increasingly clear.

IBD and Mast Cells

Mast cells are innate immune cells that are involved in IBD. Most people associate mast cells with allergy, asthma, and anaphylaxis. Indeed, mast cells are powerful “first responders” that can initiate inflammatory responses and exacerbate acute inflammation. However, mast cells are highly influenced by their microenvironment and may have divergent functions in acute inflammation compared to chronic inflammation. 

Lennon made a surprising discovery when she found IBD-prone mice deficient in mast cells actually had worse disease, indicating an anti-inflammatory, protective function for mast cells. In support, reconstitution of mast cells in mast cell-deficient IBD-prone mice reduced inflammation [1]. This discovery was echoed by other studies in chronic asthma models, in which mast cells were found to play anti-inflammatory roles [2] and additional studies highlighting the integral roles of mast cells in initiating and driving tissue repair, limiting inflammation, and regulating intestinal barrier function.

While the anti-inflammatory effects of  mast cells have been ascribed to their ability to recruit T regulatory cells and synthesize anti-inflammatory prostaglandins and lipid mediators, Lennon’s laboratory discovered that mast cells control the intestinal levels of bone morphogenetic proteins (BMPs), stabilizing their levels during tissue recovery and repair following cycles of inflammatory flares.

A member of Dr. Lennon's lab, PhD student Jane Woodrow, DVM, DACVIM (at left), is a large animal internal medicine specialist

BMPs are members of the transforming growth factor-β (TGF-β) cytokine superfamily and have both anti-inflammatory and anti-fibrotic activities in the intestine. As intestinal fibrosis is a major complication of IBD, the dual anti-inflammatory and anti-fibrotic role of BMPs suggests they play a particularly important role in the control of IBD.

Unfortunately, BMPs cannot be administered directly to patients due to their expense and short half-life. Lennon is currently studying the signaling mechanisms that control BMP concentrations in the intestine in hopes of therapeutically manipulating these pathways to increase BMP levels in IBD patients, thereby reducing pathology.

Effects of Psychological Stress on Mast Cells

Psychological stress can induce flares of IBD. Compared to the general population, IBD patients have a higher incidence of psychological disorders, which often precede the IBD diagnosis [3].  

Stressful life events are also associated with IBD onset and disease flares. The “gut-brain axis,” which is used to describe neural circuitry that facilitates bidirectional interactions between the central nervous system, the enteric nervous system, and the intestinal microbiota has been implicated in the association between psychological disorders and IBD, but the exact mechanisms contributing to increased disease risk are not understood.

Mast cells are essential mediators of the crosstalk between the enteric nervous system and the immune system. Lennon is currently investigating the mechanisms by which alterations in neuropeptide production by central and enteric neurons influence mast cell phenotype and function in her newly generated murine model that recapitulates increased susceptibility to IBD in response to psychological stress [4].

IBD Research and Clinical Gastroenterology

Lennon’s clinical curiosity about her IBD patients drives her research, and vice versa. She believes that by studying mechanisms of mast cells in clinical patients (both veterinary and human) she can better understand how these cells limit inflammation. Moreover, because mast cells behave differently in acute inflammation compared to chronic inflammation and are highly influenced by their microenvironment, her assessment of mast cell function in naturally occurring disease provides a more accurate, real-life picture of their role in inflammatory diseases.

Lennon has ongoing clinical studies to investigate mast cell phenotypes in inflammatory diseases. Supported by a Morris Animal Foundation grant, she and graduate student Dr. Jane Woodrow have recently described alterations in mast cell phenotypes and BMP expression in equine asthma.

She also has documented alterations in fatsoluble vitamin concentrations in dogs and cats with IBD. With Ryan Hospital’s high caseload, as well as proximity to Perelman School of Medicine’s Gastroenterology Division and Penn Vet’s Veterinary Clinical Investigations Center, Lennon is excited to harness the translational potential of evaluating mast cell function in the immunoregulation of inflammatory disorders across veterinary and human medicine.

[1] Lennon EM, Borst LB, Edwards LL, et al. “Mast Cells Exert AntiInflammatory Effects in an IL10-/- Model of Spontaneous Colitis.” Mediators of Inflammation 2018;2018:7817360 PMID: 29849494. [2] Morita H, Arae K, Unno H, et al. “An Interleukin-33-Mast CellInterleukin-2 Axis Suppresses Papain-Induced Allergic Inflammation by Promoting Regulatory T Cell Numbers.” Immunity 2015;43:175-86 PMID: 26200013. [3] Walker JR, Ediger JP, Graff LA, et al. “The Manitoba IBD cohort study: a population-based study of the prevalence of lifetime and 12-month anxiety and mood disorders.”  American Journal of Gastroenterol 2008;103:198997 PMID: 18796096. [4] Lennon EM, Maharshak N, Elloumi H, et al. “Early life stress triggers persistent colonic barrier dysfunction and exacerbates colitis in adult IL-10-/- mice.” Inflammatory Bowel Diseases 2013;19:712-9 PMID: 23446335
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