Suppression of epithelial proliferation and tumorigenesis by immunoglobulin Apreprint
Аннотация: Immunoglobulin A (IgA) is the most abundant antibody isotype produced across mammals and plays a specialized role in mucosal homeostasis(1). Constantly secreted into the lumen of the intestine, IgA binds commensal microbiota to regulate their colonization and function(2,3) with unclear implications for health. IgA deficiency is common in humans but is difficult to study due to its complex aetiology and comorbidities(4-8). Using genetically and environmentally controlled mice, here we show that IgA-deficient animals have increased susceptibility to endogenous colorectal tumours. Cellular and molecular analyses revealed that, in the absence of IgA, colonic epithelial cells induce antibacterial factors and accelerate cell cycling in response to the microbiota. Oral treatment with IgA was sufficient to both reduce steady-state proliferation and protect mice from tumours, but this function was due to antibody structure rather than binding specificity. In both organoid and monolayer culture systems, IgA directly suppressed epithelial growth. Co-immunoprecipitation mass spectrometry and a targeted CRISPR screen identified DMBT1 as an IgA-binding epithelial surface protein required for IgA-mediated suppression of proliferation. Together, IgA and DMBT1 regulate Notch signalling and tune the normal cycling of absorptive colonocyte progenitors. In mice, deleting the transmembrane and cytoplasmic signalling portions of DMBT1 or blocking Notch signalling was sufficient to reverse both the increased proliferation and tumour susceptibility of IgA knockouts. These experiments establish a homeostatic function for IgA in tempering physiological epithelial responses to microbiota to maintain mucosal health.
Год издания: 2023
Авторы: Gregory P. Donaldson, Gabriella L. Reis, Marwa Saad, Christopher Wichmann, Izabela Mamede, Guo Chen, Nicole L. DelGaudio, Dayu Zhang, Begüm Aydın, C. Harrer, Tiago B. R. Castro, Sergei I. Grivennikov, Bernardo Sgarbi Reis, Beth M. Stadtmueller, Gabriel D. Victora, Daniel Mucida
Издательство: Cold Spring Harbor Laboratory
Источник: bioRxiv (Cold Spring Harbor Laboratory)
Ключевые слова: Macrophage Migration Inhibitory Factor, Phagocytosis and Immune Regulation, Immune Cell Function and Interaction
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