Thumbikat, P. | bioRxiv Science

bioRxiv2026

PD-1-Dependent Modulation of Sensory Neurons by a Staphylococcus epidermidis Lipoteichoic Acid Drives Analgesia

BackgroundImmune checkpoint receptors regulate adaptive immunity but are increasingly recognized as modulators of neuroimmune interactions. The upstream signals that induce neuronal checkpoint pathways during inflammation and their functional relevance in inflammatory pain remain incompletely understood. We investigated whether a defined commensal-derived molecule engages a neuroimmune checkpoint axis to modulate inflammatory pain. MethodsSELTA, a lipoteichoic acid purified from a commensal Staphylococcus epidermidis strain, was evaluated for TLR2-dependent activity, regulation of Pdcd1 transcription and PD-1 protein expression in dorsal root ganglion (DRG) neurons, effects on intracellular calcium signaling, and behavioral outcomes in experimental autoimmune prostatitis (EAP) a model of inflammation-induced chronic pelvic pain. Conditional Pdcd1 deletion was performed in sensory neurons (Advillin-Cre) and CD4 T cells to determine cell-specific requirements. ResultsSELTA selectively activated TLR2/6 signaling and increased Pdcd1 transcription and PD-1 protein expression in DRG neurons under inflammatory conditions. SELTA enhanced phosphorylation of PD-1 at tyrosine 248 and significantly reduced ATP-evoked intracellular Ca{superscript 2} responses in mouse primary sensory neurons. Pharmacologic neutralization of PD-1 abrogated SELTA-mediated suppression of calcium signaling. In vivo, SELTA produced concentration-dependent attenuation of pelvic hypersensitivity in EAP. Conditional deletion of PD-1 in vivo in Advillin-expressing sensory neurons or CD4 T cells significantly reduced SELTA-induced analgesia, while combined deletion did not further diminish the effect. ConclusionsThese findings identify a commensal-derived lipoteichoic acid that engages a TLR2/6-associated pathway linked to inducible neuronal PD-1 signaling to restrain inflammatory nociceptor activity. The results define a neuroimmune checkpoint mechanism that modulates inflammatory pain and extend PD-1 signaling beyond its established role in adaptive immunity.

neuroscience↗

bioRxiv2021

Mast cell function in prostate inflammation, fibrosis, and smooth muscle cell dysfunction

Intraurethral inoculation of mice with uropathogenic E. coli (CP1) results in prostate inflammation, fibrosis, and urinary dysfunction, recapitulating some but not all of the pathognomonic clinical features associated with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS). In both patients with LUTS and in CP1-infected mice, we observed increased numbers and activation of mast cells and elevated levels of prostate fibrosis. Therapeutic inhibition of mast cells and the histamine 1 receptor in the mouse model resulted in reduced mast cell activation in the prostate and significant alleviation of urinary dysfunction. Treated mice showed reduced prostate fibrosis, less infiltration of immune cells, and decreased inflammation. In addition, as opposed to symptomatic CP1-infected mice, treated mice showed reduced myosin light chain (MLC)-2 phosphorylation, a marker of prostate smooth muscle contraction. These results show that mast cells play a critical role in the pathophysiology of urinary dysfunction and may be an important therapeutic target for men with BPH/LUTS. NEW AND NOTEWORTHYLUTS-associated BPH is derived from a combination of immune activation, extracellular matrix remodeling, hyperplasia, and smooth muscle cell contraction in prostates of men. Using a mouse model, we describe the importance of mast cells in regulating these multiple facets involved in the pathophysiology of LUTS. Mast cell inhibition alleviates both pathology and urinary dysfunction in this model suggesting the potential for mast cell inhibition as a therapeutic that prevents and reverses pathology and associated symptomology.

cell biology↗