Clinical rheumatology · 2026
NETs mediate neuropathic pain in PSS-PN by participating in inflammatory injury to the vasa nervorum.
СтатьяНазвание и аннотация: Перевод в очереди
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Xu Liying, Wei Jiying, Chen Donghua, Xu Bihua, Liu Yuxin, Fu Xiangmingyang, Zheng Jiaman, Tang Ling, Lin Junhao, Yang Yi, Li Wei, Yuan Chao
Аннотация
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.
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.