Growth hormone releasing hormone signaling promotes Th17 cell differentiation and autoimmune inflammation

Lin Du, Bo Man Ho, Linbin Zhou, Yolanda Wong Ying Yip, Jing Na He, Yingying Wei, Clement C. Tham, Sun On Chan, Andrew V. Schally, Chi Pui Pang, Jian Li () and Wai Kit Chu ()
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Lin Du: The Chinese University of Hong Kong
Bo Man Ho: The Chinese University of Hong Kong
Linbin Zhou: The Chinese University of Hong Kong
Yolanda Wong Ying Yip: The Chinese University of Hong Kong
Jing Na He: The Chinese University of Hong Kong
Yingying Wei: The Chinese University of Hong Kong
Clement C. Tham: The Chinese University of Hong Kong
Sun On Chan: The Chinese University of Hong Kong
Andrew V. Schally: Veterans Affairs Medical Center
Chi Pui Pang: The Chinese University of Hong Kong
Jian Li: The Chinese University of Hong Kong
Wai Kit Chu: The Chinese University of Hong Kong

Nature Communications, 2023, vol. 14, issue 1, 1-15

Abstract: Abstract Dysregulation of Th17 cell differentiation and pathogenicity contributes to multiple autoimmune and inflammatory diseases. Previously growth hormone releasing hormone receptor (GHRH-R) deficient mice have been reported to be less susceptible to the induction of experimental autoimmune encephalomyelitis. Here, we show GHRH-R is an important regulator of Th17 cell differentiation in Th17 cell-mediated ocular and neural inflammation. We find that GHRH-R is not expressed in naïve CD4+ T cells, while its expression is induced throughout Th17 cell differentiation in vitro. Mechanistically, GHRH-R activates the JAK-STAT3 pathway, increases the phosphorylation of STAT3, enhances both non-pathogenic and pathogenic Th17 cell differentiation and promotes the gene expression signatures of pathogenic Th17 cells. Enhancing this signaling by GHRH agonist promotes, while inhibiting this signaling by GHRH antagonist or GHRH-R deficiency reduces, Th17 cell differentiation in vitro and Th17 cell-mediated ocular and neural inflammation in vivo. Thus, GHRH-R signaling functions as a critical factor that regulates Th17 cell differentiation and Th17 cell-mediated autoimmune ocular and neural inflammation.

Date: 2023
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DOI: 10.1038/s41467-023-39023-1

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