AUTHOR=Karim Adil , Garg Rashi , Saikia Biman , Tiwari Abha , Sahu Smrity , Malhotra Mehak , Minz Ranjana W. , Rawat Amit , Singh Surjit , Suri Deepti TITLE=Unraveling the unphosphorylated STAT3–unphosphorylated NF-κB pathway in loss of function STAT3 Hyper IgE syndrome JOURNAL=Frontiers in Immunology VOLUME=15 YEAR=2024 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1332817 DOI=10.3389/fimmu.2024.1332817 ISSN=1664-3224 ABSTRACT=Background

Patients 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.

Objective

This study aims to elucidate the role of unphosphorylated STAT3–unphosphorylated NF-κB (uSTAT3–uNF-κB) activation pathway in LOF STAT3 HIES patients.

Methodology

The 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.

Results

A 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.

Conclusion

The 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.