NETs mediate neuropathic pain in PSS-PN by participating in inflammatory injury to the vasa nervorum.

OBJECTIVES

To explore how neutrophil extracellular traps (NETs) mediate neuropathic pain in primary Sjögren's syndrome-associated peripheral neuropathy (pSS-PN).

METHODS

We analyzed clinical features in pSS-PN (n = 6) by DN4 Questions, Electromyography examination and sural nerve biopsies from six pSS-PN patients and six traumatic amputees using histology, immunohistochemistry (IHC), transmission electron microscopy (TEM), and immunofluorescence (IF) for NETs markers (cit-H3/MPO). And we created a model of pSS-PN. Pain behaviors were assessed, plasma cit-H3 was measured by ELISA, and hindlimb perfusion was quantified via laser speckle imaging. To inhibit NETosis, DNase I was administered intravenously.

RESULTS

PSS-PN patients exhibited neuropathic pain, nerve conduction deficits, reduced nerve fiber density, and inflammatory vasa nervorum injury with significant cit-H3/MPO accumulation. NOD. Aire⁻/⁻ mice developed mechanical allodynia (1.885 vs. 2.497, P < 0.001 vs. C57BL/6 J; 1.885 vs. 2.367 P < 0.01 vs. NOD WT) and thermal hyperalgesia (6.993 vs. 8.585, P < 0.05 vs. C57BL/6 J; 6.93 vs. 8.815 P < 0.05 vs. NOD WT), accompanied by elevated plasma cit-H3 (44.61 vs. 27.49, P < 0.0001 vs. C57BL/6 J; 44.61 vs. 30.96 P < 0.0001 vs. NOD WT), sciatic nerve NETs deposition (44.61 vs. 35.60, P < 0.0001 24 vs. 18 weeks, NOD. Aire⁻/⁻), and increased hindlimb perfusion. DNase I treatment effectively reduced plasma cit-H3, alleviated pain behaviors, mitigated microvascular damage, and normalized perfusion.

CONCLUSION

NETs drive peripheral neuropathy in pSS by inducing vasa nervorum inflammation and microcirculatory dysfunction, leading to neuropathic pain. These findings identify NETs as a key mechanistic link, biomarker, and promising therapeutic target in pSS-PN. Highlights • Higher consumption of ultra-processed foods is associated with increased disease activity in patients with ankylosing spondylitis • A novel murine model (NOD. Aire⁻/⁻) recapitulates human pSS-PN, exhibiting spontaneous neuropathic pain, peripheral nerve inflammation, elevated NETs, and microcirculatory dysfunction; • DNase1-mediated NETs degradation alleviates neuropathic pain and normalizes hindlimb perfusion, supporting NETs as a promising therapeutic target in pSS-PN.