Yesupatham, S. K. | bioRxiv Science

bioRxiv2026

Satellite glial translatome reprograms to favor mitochondrial and vesicular signaling under pelvic pain conditions

Sensory satellite glial cells actively contribute to inflammatory and neuropathic pain, but their roles in pelvic pain remain unclear. This study examined how the active translating mRNAs in sensory SGCs change during pelvic pain symptoms using translating ribosome affinity purification followed by RNA sequencing (TRAP-seq) in a chronic pelvic pain (CPP) mouse model. Our data showed that SGCs exhibit sex-specific translatome patterns at baseline, which were reprogrammed in CPP conditions under the control of eukaryotic translation initiation factor 4E (Eif4e). In CPP conditions, sensory SGCs exhibit increased translation of mitochondrial and vesicular genes and suppression of immune genes in both sexes; an anti-inflammatory cytokine profile was detected in female pelvic sensory ganglia. We are the first to characterize SGC translatome in pelvic pain conditions and to report sex differences in SGC translatome. Our data suggested that mitochondrial and vesicular gene translation in sensory SGCs may be important to afferent hypersensitivity.

neuroscience↗

bioRxiv2023

Mouse Homolog of Human IRF8G388S Mutation Provides Novel Insight into Osteoclastogenesis and Tooth Root Resorption

Previously, we reported a novel mutation in the Interferon Regulatory Factor 8 (IRF8) gene associated with multiple idiopathic cervical root resorption (MICRR), an aggressive form of tooth root resorption mediated by increased osteoclast activity. The IRF8 G388S variant in the highly conserved C-terminal motif is predicted to alter the protein structure, likely impairing IRF8 function. To investigate the molecular basis of MICRR and IRF8 function, we generated Irf8 knock-in (KI) mice using CRISPR/Cas9 modeling the human IRF8G388S mutation. The heterozygous (Het) and homozygous (Homo) Irf8 KI mice showed no gross morphological defects, and the development of hematopoietic cells was unaffected and similar to that in wild-type (WT) mice. The Irf8 KI Het and Homo mice showed no difference in macrophage gene signatures important for antimicrobial defenses and inflammatory cytokine production. Consistent with the phenotype observed in MICRR patients, Irf8 KI Het and Homo mice demonstrated significantly increased osteoclast formation and resorption activity in vivo and in vitro when compared to WT mice. The oral ligature inserted Irf8 KI Het and Homo mice displayed increased osteoclast-mediated alveolar bone loss and tooth root resorption compared to WT mice. The increased osteoclastogenesis noted in KI mice is due to the inability of mutant Irf8 G388S isoform to negatively inhibit NFATc1-dependent transcriptional activation and downstream osteoclast specific transcripts. This translational study delineates the IRF8 domain important for osteoclast function and provides novel insights into the IRF8 mutation associated with MICRR. Irf8G388S mutation mainly affects osteoclastogenesis while sparing immune cell development and function. The Irf8 KI mice serve as a novel translational model for studying the etiopathology of MICRR and developing targeted therapies for MICRR and other skeletal disorders mediated by increased osteoclast activity.

genetics↗