AJP - Gastrointestinal and Liver Physiology

Callejas, Blanca E.; Sousa, James A.; Flannigan, Kyle L.; Wang, Arthur; Higgins, Eve; Herik, Aydin I.; Li, Shuhua; Rajeev, Sruthi; Rosentreter, Ryan; Panaccione, Remo; McKay, Derek M.

doi: 10.1152/ajpgi.00159.2024pmid: 39378308

Interleukin-4 activated human macrophages (M(IL4) promote epithelial wound healing and exert an anti-colitic effect in a murine model. Blood monocyte-derived M(IL4)s from healthy donors and individuals with Crohn's disease had increased mRNA expression of the calcitonin gene-related peptide (CGRP) receptor chain, RAMP1, raising the issue of neural modulation of the M(IL4)s reparative function. Thus, human (MIL4)s were treated with CGRP and the cells phagocytotic, epithelial wound repair and anti-colitic functions were assessed. Initial studies confirmed up-regulation of expression of the CGRP receptor, which was localized to the cell surface and was functional as determined by CGRP-evoked increases in cAMP. M(IL4,CGRP)s had increased mannose receptor (CD206) and FcgRIIa (CD32a) mRNA expression, a subtle, but significant increase in phagocytosis, and decreased chemokine production following exposure to E. coli. When delivered systemically (106 cells, ip.) to oxazolone-treated rag1-/- mice, M(IL4,CGRP) had an anti-colitic effect superior to M(IL4)s from the same blood donor. Conditioned medium (CM) from M(IL4,CGRP) had increased amounts of TGFb and increased wound-healing capacity compared to matched M(IL4)-CM in the human CaCo2 epithelial cell line in vitro wounding assay. Moreover, M(IL4,CGRP)s displayed increased cyclooxygenase (COX)-1 and prostaglandin D2, and CM from M(IL4,CGRP)s treated with indomethacin or SC-560 to inhibit COX1 activity failed to promote repair of wounded CaCo2 cell monolayers. These data confirm the human M(IL4)s' anti-colitic effect that was enhanced by CGRP, and may be partially dependent on macrophage COX1/PDG2 activity. Thus, input from neurone-derived molecules is a local modifier capable of boosting the anti-colitic effect of autologous M(IL4) transfer.

Ramírez-Maldonado, Luis M.; Guerrero-Castro, Julio; Rodríguez-Mejía, José L.; Cárdenas-Conejo, Yair; Bonales-Alatorre, Edgar O.; Valencia-Cruz, Georgina; Anguiano-García, Paulina T.; Vega-Juárez, Irving I.; Dagnino-Acosta, Adán; Ruvalcaba-Galindo, Jessica; Valdez-Morales, Eduardo E.; Ochoa-Cortes, Fernando; Barajas-Espinosa, Alma; Guerrero-Alba, Raquel; Liñán-Rico, Andrómeda

Kelly, Cecelia; Sartor, R. Balfour; Rawls, John F.

doi: 10.1152/ajpgi.00252.2024pmid: 39499254

The inflammatory bowel diseases (IBD) occur in genetically susceptible individuals that mount inappropriate immune responses to their microbiota leading to chronic intestinal inflammation. The natural history of IBD progression begins with early subclinical stages of disease that occur before clinical diagnosis. Improved understanding of those early subclinical stages could lead to new or improved strategies for IBD diagnosis, prognostication or prevention. Here we review our current understanding of the early subclinical stages of IBD in humans including studies from first-degree relatives of IBD patients and members of the general population who go on to develop IBD. We also discuss representative mouse models of IBD that can be used to investigate disease dynamics and host-microbiota relationships during these early stages. In particular, we underscore how mouse models of IBD that develop disease later in life with variable penetrance may present valuable opportunities to discern early subclinical mechanisms of disease before histological inflammation and other severe symptoms become apparent.

Nielsen, Malte Hasle; Nøhr-Meldgaard, Jacob; Møllerhøj, Mathias Bonde; Oró, Denise; Pors, Susanne E.; Andersen, Maja Worm; Kamzolas, Ioannis; Petsalaki, Evangelia; Vacca, Michele; Harder, Lea Mørch; Perfield, James W.; Veidal, Sanne; Hansen, Henrik H.; Feigh, Michael

doi: 10.1152/ajpgi.00110.2024

Yun, C. Chris

doi: 10.1152/ajpgi.00355.2024pmid: 39589437

Penrod, Sarah; Tang, Xiaofang; Moon, Changsuk; Whitsett, Jeffrey A.; Naren, Anjaparavanda P.; Huang, Yunjie

doi: 10.1152/ajpgi.00066.2024pmid: 39641142

Membrane proteins, such as the Cystic Fibrosis Transmembrane-conductance Regulator (CFTR), play a crucial role in gastrointestinal functions and heath. Endoplasmic reticulum (ER) membrane protein complex (EMC), a multi-subunit insertase, mediates the incorporation of membrane segments into lipid bilayers during protein synthesis. Whether EMC regulates membrane proteins’ processing and function in intestinal epithelial cells remains unclear. To investigate the role of EMC in the intestinal epithelium, we generated mice in which EMC subunit 3 (EMC3) was deleted in intestinal epithelial cells (EMC3ΔIEC). EMC3ΔIEC mice were viable but notable smaller compared to their wildtype littermates. While intestinal structure was generally maintained, EMC3ΔIEC crypts exhibited altered morphology, particularly at the base of the crypts with decreased goblet cells and paneth cells. Levels of multiple polytopic membrane proteins, including CFTR, were decreased in EMC3-deficient epithelial cells. Several calcium ATPase pumps were downregulated, and calcium mobilization was impaired in EMC3ΔIEC enteroids. CFTR-mediated organoid swelling in EMC3ΔIEC mice was impaired in response to both cAMP-dependent signaling and calcium-secretagogue stimulation. Our study demonstrated that EMC plays a critical role in maintaining intestinal epithelium homeostasis by regulating membrane protein biogenesis and intracellular calcium homeostasis. Maintaining intracellular calcium homeostasis may be a universal cellular function regulated by EMC.