Kidney Week

Abstract: TH-PO0654

MESH1 Is a Novel Regulator of cGAS/STING-Mediated Type I Interferon Generation in Myeloid Cells to Attenuate Autoimmune Glomerulonephritis

Session Information

• Glomerular Diseases: Immunopathogenesis and Targeted Therapeutics
  November 06, 2025 | Location: Exhibit Hall, Convention Center
  Abstract Time: 10:00 AM - 12:00 PM

Category: Glomerular Diseases

• 1401 Glomerular Diseases: Mechanisms, including Podocyte Biology

Authors

• Chen, Yanting, Duke University, Durham, North Carolina, United States

Yanting Chen, PhD

• Zhang, Yang, Duke University, Durham, North Carolina, United States

Yang Zhang, MD, PhD

• Mestre, Alexander, Duke University, Durham, North Carolina, United States

Alexander Mestre

• Wu, Jianli, Duke University, Durham, North Carolina, United States

Jianli Wu

• Ren, Jiafa, Nanjing Medical University, Nanjing, Jiangsu, China

Jiafa Ren, MD, PhD

• Wu, Chia-Chun, Duke University, Durham, North Carolina, United States

Chia-Chun Wu, MD

• Crowley, Steven D., Duke University, Durham, North Carolina, United States

Steven D. Crowley, MD

• Zhou, Pei, Duke University, Durham, North Carolina, United States

Pei Zhou, PhD

• Chi, Jen-Tsan, Duke University, Durham, North Carolina, United States

Jen-Tsan Chi, MD, PhD

• Privratsky, Jamie R., Duke University, Durham, North Carolina, United States

Jamie R. Privratsky, MD, PhD

Background

The stringent response is the main stress adaptive mechanism in bacteria to alter gene transcription and redirect metabolic resources during nutrient deprivation and stress. Our collaborators recently identified Metazoan SpoT Homologue 1 (MESH1), a homologue of the bacterial enzyme SpoT involved in the stringent response, as the first mammalian cytosolic NADPH phosphatase in vitro. However, the in vivo function of MESH1 and its relevant physiologic substrates is not known. Our group has determined that MESH1 can limit the type I interferon (IFN-I) response in macrophages. As IFN-I plays a prominent role in autoimmune-mediated glomerulonephritis, a major cause of chronic kidney disease (CKD), we hypothesized that macrophage MESH1 would limit the development of autoimmune glomerulonephritis.

Methods

Transgenic mice: global MESH1 WT and KO mice, LysM-Cre+ / MESH1^fl/fl (MESH1 MKO) and littermate LysM-Cre(-) / MESH1^fl/fl (MESH1 MWT) mice. Model: nephrotoxic serum (NTS) nephritis. Primary outcome: urinary albumin excretion. Secondary outcomes: mRNA expression of tubular injury markers and fibrotic protein expression. Exploratory analysis: IFN-I levels were quantified in kidney tissue by ELISA. Bone marrow-derived macrophages (BMDMs) were stimulated with cytosolic DNA to assess cGAS/STING pathway activation and IFN-β production.

Results

BMDMs from global MESH1-deficient mice demonstrated amplified IFN-I induction and STING activation upon cytosolic DNA stimulation. Mechanistically, MESH1 reduced STING-mediated IFN-I by reducing cellular levels of cyclic GMP-AMP synthase (cGAS)-generated 2’3’-cGAMP, which subsequently activates STING. MESH1 reduces 2’3’-cGAMP levels by enzymatically dephosphorylating a linear dinucleotide intermediate required for its synthesis. In vivo, global MESH1 KO mice developed increased albuminuria following NTS nephritis. MESH1 MKO mice also showed increased albuminuria, tubular injury, fibrosis, and intrarenal IFN-β production.

Conclusion

These results identify MESH1 as a novel checkpoint in myeloid cell to suppresses the cGAS/STING/type I interferon axis, which has implications for autoimmune-mediated glomerulonephritis

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.202532kj9z96