Triggering Receptor Expressed on Myeloid Cells 2+ Macrophages Promote Pancreatic Regeneration Through Cholesterol-Metabolism Reprogramming and Hedgehog Signaling Activation Following Acute Pancreatitis

Background & aims: Macrophage phenotypic transition plays a crucial role in inflammation resolution and tissue repair following acute pancreatitis. Triggering receptor expressed on myeloid cells 2, a damage-sensing immune receptor expressed in macrophages, has been associated with tissue repair in various disease contexts. Here, we aimed to investigate the role of triggering receptor expressed on myeloid cells 2⁺ macrophages in pancreatic regeneration following acute pancreatitis.

Methods: We used single-cell Sequencing and immunohistochemistry to identify triggering receptor expressed on myeloid cells 2⁺ macrophage subpopulation and combined lineage tracing to confirm its origin. Circulating soluble triggering receptor expressed on myeloid cells 2 levels were assessed in acute pancreatitis clinical cohorts. Functional analysis was conducted using LysM^CreTrem2^fl/fl mice. Transcriptomic profiling and pharmacologic assays elucidated molecular mechanisms.

Results: We show that monocyte-derived triggering receptor expressed on myeloid cells 2⁺ macrophages accumulate in the peri-acinar-to-ductal metaplasia region during acute pancreatitis and are essential for pancreatic regeneration. Genetic ablation of triggering receptor expressed on myeloid cells 2 impaired pancreatic regeneration, characterized by persistent inflammation, stromal deposition, and compromised acinar redifferentiation and proliferation. Mechanistically, triggering receptor expressed on myeloid cells 2 deficiency impeded macrophage phenotype transition toward an anti-inflammatory/proreparative state, which is associated with Cholesterol metabolic reprogramming. Furthermore, triggering receptor expressed on myeloid cells 2 deficiency reduced the paracrine expression of Desert Hedgehog, thereby attenuating Hedgehog signaling in progenitor-like epithelial cells. Pharmacologic activation of the Hedgehog signaling rescued pancreatic regeneration and stromal remodeling. Immunohistochemical analysis confirmed the presence of triggering receptor expressed on myeloid cells 2⁺ macrophages in pancreatic tissues from patients with acute pancreatitis, and serum-soluble triggering receptor expressed on myeloid cells 2 levels inversely correlated with disease severity, further confirming the clinical relevance of triggering receptor expressed on myeloid cells 2⁺ macrophages in acute pancreatitis.

Conclusions: Triggering receptor expressed on myeloid cells 2⁺ macrophages play a protective role in pancreatic repair. Targeting the triggering receptor expressed on myeloid cells 2/Desert Hedgehog axis offers a therapeutic framework for modulating macrophage function to treat pancreatitis or pancreatic insufficiency.