Defining the Role of the Peritoneum in Disease

About This Grant

PROJECT SUMMARY / ABSTRACT Mast cell activation syndrome (MCAS) presents with a variety of clinical manifestations affecting multiple organ systems in the body. In tissue-specific pathologies such as allergy and chronic spontaneous urticaria (CSU), mast cells are activated by the crosslinking of IgE antibodies to the high-affinity receptor FcRI on their cell surface, leading to the release of various effector molecules such as histamine, leukotrienes, and prostaglandins. As such, IgE blockade has been an effective therapy for these outcomes as seen by the approval of omalizumab for food allergies and dupilumab for CSU by the FDA. However, MCAS can present with both IgE-dependent and IgE-independent symptoms, the latter of which have been poorly defined mechanistically. One example is visceral pain, which affects 20-40% of the population and is extremely debilitating and detrimental to the overall quality of life, but is very difficult to localize and lacks effective treatment strategies. Recently, Mas-related G protein-coupled receptor member X2 (MRGPRX2) – the human ortholog of murine MrgprB2 – has emerged as a new IgE-independent mechanism by which mast cells can be activated. MRGPRX2 on mast cells can respond to many different endogenous and exogenous ligands including neuropeptides like substance P (SP), suggesting it may have unique roles across organ systems. Preliminary experiments have shown that MRGPRX2+ mast cells and Trpv1+ sensory neurons are key mediators of bladder-colon irritation. Nonetheless, whether there is a central location where mast cells can be activated and spread pathology to other compartments remains an open question. One understudied region in the body is the peritoneum, which contains mast cells, is densely innervated by sensory neurons, and can feed into circulation through the lymphatic system and allow the transport of molecules to distal tissues. Peritoneal mast cells have been widely utilized in vitro to study other cellular processes such as skin inflammation and tissue repair, raising the question of whether they can contribute to any disease processes in vivo and if their local activation within the peritoneum can lead to pathology in other organ systems. Furthermore, sensory neurons have been shown to induce pain syndromes through the release of neuropeptides such as SP, which has the capacity to act on mast cells. Put together, this provokes the hypothesis that mast cells and sensory neurons in the peritoneum may be central mediators of pathology across multiple organ systems. This project will combine behavioral assays, peritoneal mast cell transplantation, and neural tracing to investigate the contribution of MRGPRX2/MrgprB2+ mast cells (Aim 1) and TRPV1+ sensory neurons (Aim 2) within the peritoneal compartment to visceral pain. Collectively, these studies will provide novel insight into IgE-independent mast cell activation, clarify neuroimmune axes facilitating visceral hypersensitivity, and establish whether the peritoneum is an active neuroimmune interface for systemic pathology. These findings will explain how a variety of pathologies can present concurrently in patients with MCAS and provide a new framework to study mast cell-related disorders.