Tuft cells resolve pancreatic injury through a Type 2 Immune circuit

Abstract public domain (NIH RePORTER)

Chronic pancreatitis (CP) is a progressive disease characterized by inflammation, stromal deposition, and loss of functional acinar tissue leading to exocrine insufficiency, malnutrition, and diabetes. CP also predisposes to pancreatic ductal adenocarcinoma (PDAC), an aggressive cancer with one of the highest mortality-to- incidence rates of any solid tumor. Current management includes risk-factor modification, pain control, and support of pancreatic endocrine and/or exocrine failure. Surgery may help prevent further progression but is not curative. Currently, it is not known how the normal pancreas successfully mitigates injury. CP may result when an acute episode overcomes the endogenous wound repair response or when an individual is unable to mount an efficient immune resolution response. Chronic injury in the pancreas results in replacement of acinar cells with cells of ductal character in a process called acinar to ductal metaplasia (ADM). Recently, our group discovered that ADM results in the de novo formation of chemosensory tuft cells (TCs), revealing an amazing amount of plasticity in the adult pancreas. TCs are known to play diverse protective roles in infection and tumorigenesis and have been shown to secrete IL-25 and PGD2 to mitigate infection by amplifying a Type 2 immune cell signaling circuit. Type 2 immunity also plays a critical role in wound repair. Our preliminary data show that CP is characterized by Type 2 cytokines (IL-13, IL-25, IL-33) and immune cells (ILC2s, TH2 T cells). ADM TCs express both hematopoietic prostaglandin D2 synthase (HPGDS) and IL-25 and either TC or IL-25 ablation exacerbates tissue injury. We hypothesize that ADM TCs secrete PGD2 and IL-25 to induce a tissue- restorative Type 2 immune response, creating a “niche” associated with less severe injury and more rapid healing. The following specific aims will test this hypothesis. AIM 1. Determine the role of ADM tuft cells in Type 2 immune infiltration during tissue injury and repair in the mouse. We hypothesize that TCs amplify an IL-33-induced, IL-13+ Type 2 immune cell infiltrate (ILC2 and TH2 T cells) through PGD2 and/or IL-25 resulting in less tissue damage and more rapid post-injury healing. We will use genetically engineered mouse models (tuft cell, HPGDS, IL-25, IL-33, or IL-13 ablation) and CP models to determine if a TC-type 2 immune circuit mitigates injury. AIM 2. Perform a multimodal analysis to determine the role of tuft cells in human CP. We hypothesize that if TCs and Type 2 immune cells are involved in pancreatic repair, then they will localize to areas of ADM as compared to highly inflamed, fibrotic regions. TC abundance and immune infiltrate will be quantified and transcriptomically characterized in a large cohort of patient CP samples to identify differences between normal pancreata, TC-high ADM tissue, and highly fibrotic, inflamed tissue within a patient using single nucleus and spatial approaches. Impact: Identifying TC-stromal relationships that function in immune modulation and injury resolution is relevant to designing strategies to co-opt these systems for patient benefit. Success in these studies could produce a roadmap for defining the role of TCs in wound healing in other tissues.

Public health relevance public domain (NIH RePORTER)

Chronic pancreatitis is a severe inflammatory condition characterized by inflammation, stromal deposition, and loss of functional acinar tissue leading to exocrine insufficiency, malnutrition, and diabetes. Interventions are lacking because the mechanisms underlying tissue injury and repair are unknown, however, we have discovered that injury-induced metaplasia in the pancreas results in the formation of chemosensory tuft cells that express immune modulators and mitigate injury. We anticipate that the proposed application will advance our understanding of the mechanisms regulating tissue injury, metaplasia, and wound repair, the role tuft cells, tuft cell effectors, and Type 2 immunity in pancreatitis, and will identify new therapeutic targets as well as beneficial pathways to co-opt for patient benefit.