LPAR1 regulates enteric nervous system function through glial signaling and contributes to chronic intestinal pseudo-obstruction
Mohammad M. Ahmadzai, … , Roberto De Giorgio, Brian D. Gulbransen
Mohammad M. Ahmadzai, … , Roberto De Giorgio, Brian D. Gulbransen
Published February 15, 2022
Citation Information: J Clin Invest. 2022;132(4):e149464. https://doi.org/10.1172/JCI149464.
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Research Article Gastroenterology Neuroscience

LPAR1 regulates enteric nervous system function through glial signaling and contributes to chronic intestinal pseudo-obstruction

Abstract

Gastrointestinal motility disorders involve alterations to the structure and/or function of the enteric nervous system (ENS) but the causal mechanisms remain unresolved in most cases. Homeostasis and disease in the ENS are processes that are regulated by enteric glia. Signaling mediated through type I lysophosphatidic acid receptors (LPAR1) has recently emerged as an important mechanism that contributes to disease, in part, through effects on peripheral glial survival and function. Enteric glia express LPAR1 but its role in ENS function and motility disorders is unknown. We used a combination of genetic, immunohistochemical, calcium imaging, and in vivo pharmacological approaches to investigate the role of LPAR1 in enteric glia. LPAR1 was enriched in enteric glia in mice and humans and LPA stimulated intracellular calcium responses in enteric glia, subsequently recruiting activity in a subpopulation of myenteric neurons. Blocking LPAR1 in vivo with AM966 attenuated gastrointestinal motility in mice and produced marked enteric neuro- and gliopathy. Samples from humans with chronic intestinal pseudo-obstruction (CIPO), a severe motility disorder, showed reduced glial LPAR1 expression in the colon and ileum. These data suggest that enteric glial LPAR1 signaling regulates gastrointestinal motility through enteric glia and could contribute to severe motility disorders in humans such as CIPO.

Authors

Mohammad M. Ahmadzai, Jonathon L. McClain, Christine Dharshika, Luisa Seguella, Fiorella Giancola, Roberto De Giorgio, Brian D. Gulbransen

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Figure 4

LPAR1 activation drives Ca2+ responses in myenteric glia.

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LPAR1 activation drives Ca2+ responses in myenteric glia. Representative...
Representative examples of Ca2+ responses in single myenteric ganglia from the colons of Wnt1Cre2 GCaMP5g-tdT mice. (A, C, and E) tdT fluorescence (red, left panels) is high in glia and low in neurons in Wnt1Cre2 GCaMP5g-tdT mice. GCaMP5g fluorescence (center and right panels) is broadly distributed among neurons and glia. Panels in A and B (centers) and E (center and right) display representative responses (GCaMP5g fluorescence) to stimuli as a temporal color-coded projection. Representative examples of glia (yellow arrows) and neurons (asterisks) that responded to electrical field stimulations (EFS), ADP, or EFS/18:1 LPA are highlighted (A, C, and E, respectively). Note that EFS evokes broad Ca2+ activity among enteric neurons followed by activity in enteric glia, while responses to ADP and LPA are predominantly confined to glia. (B, D, and F) Quantification of neuron and glial Ca2+ responses evoked by EFS, ADP, and LPA in myenteric ganglia, respectively. (G) Summary of EFS, ADP, and LPA-mediated Ca2+ responses in myenteric neurons and glia. (H) Summary data showing neuronal and glial responses to various concentrations of LPA in samples from male and female mice. (I) Summary data showing neuronal and glial responses to 1 μM LPA in control (CTRL) and fluoroacetate-treated (FA) tissues and (J) their stratification between male and female mice. n = 141–1073 glia and 153–1064 neurons in A–J; *P < .05, **P < .01, and ****P < .0001, by 2-tailed t test and 1-way ANOVA. Scale bars in A and E = 25 μm and in C = 50 μm.