Frontiers in Immunology (Aug 2024)

Unraveling the unphosphorylated STAT3–unphosphorylated NF-κB pathway in loss of function STAT3 Hyper IgE syndrome

  • Adil Karim,
  • Rashi Garg,
  • Biman Saikia,
  • Abha Tiwari,
  • Smrity Sahu,
  • Mehak Malhotra,
  • Ranjana W. Minz,
  • Amit Rawat,
  • Surjit Singh,
  • Deepti Suri

DOI
https://doi.org/10.3389/fimmu.2024.1332817
Journal volume & issue
Vol. 15

Abstract

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BackgroundPatients with loss of function signal transducer and activator of transcription 3-related Hyper IgE Syndrome (LOF STAT3 HIES) present with recurrent staphylococcal skin and pulmonary infections along with the elevated serum IgE levels, eczematous rashes, and skeletal and facial abnormalities. Defective STAT3 signaling results in reduced Th17 cells and an impaired IL-17/IL-22 response primarily due to a compromised canonical Janus kinase-signal transducer and activator of transcription (JAK–STAT) pathway that involves STAT3 phosphorylation, dimerization, nuclear translocation, and gene transcription. The non-canonical pathway involving unphosphorylated STAT3 and its role in disease pathogenesis, however, is unexplored in HIES.ObjectiveThis study aims to elucidate the role of unphosphorylated STAT3–unphosphorylated NF-κB (uSTAT3–uNF-κB) activation pathway in LOF STAT3 HIES patients.MethodologyThe mRNA expression of downstream molecules of unphosphorylated STAT3–unphosphorylated NF-κB pathway was studied in five LOF STAT3 HIES patients and transfected STAT3 mutants post-IL-6 stimulation. Immunoprecipitation assays were performed to assess the binding of STAT3 and NF-κB to RANTES promoter.ResultsA reduced expression of the downstream signaling molecules of the uSTAT3–uNF-κB complex pathway, viz., RANTES, STAT3, IL-6, IL-8, ICAM1, IL-8, ZFP36L2, CSF1, MRAS, and SOCS3, in LOF STAT3 HIES patients as well as the different STAT3 mutant plasmids was observed. Immunoprecipitation studies showed a reduced interaction of STAT3 and NF-κB to RANTES in HIES patients.ConclusionThe reduced expression of downstream signaling molecules, specially RANTES and STAT3, confirmed the impaired uSTAT3–uNF-κB pathway in STAT3 LOF HIES. Decreased levels of RANTES and STAT3 could be a significant component in the disease pathogenesis of Hyper IgE Syndrome.

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