TY - JOUR
T1 - The local molecular signature of human peripheral neuropathic pain
AU - Sandy-Hindmarch, Oliver P.
AU - Chang, Pao Sheng
AU - Scheuren, Paulina S.
AU - De Schoenmacker, Iara
AU - Hubli, Michèle
AU - Loizou, Constantinos
AU - Wirth, Stephan
AU - Mahadevan, Devendra
AU - Wiberg, Akira
AU - Furniss, Dominic
AU - Calvo, Margarita
AU - Bennett, David L.H.
AU - Denk, Franziska
AU - Baskozos, Georgios
AU - Schmid, Annina B.
N1 - Publisher Copyright:
© 2024 The Author(s).
PY - 2024
Y1 - 2024
N2 - Focal nerve injuries are often associated with neuropathic pain. Preclinical research suggests altered neuroimmune signalling underlies such neuropathic pain; however, its cause remains poorly understood in humans. In this multicentre cohort study, we describe the local cellular and molecular signature of neuropathic pain at the lesion site, using Morton's neuroma as a human model system of neuropathic pain (n = 22; 18 women) compared with nerves from participants without nerve injury (n = 11; 4 women). Immunofluorescent staining revealed demyelination and chronic infiltration of immune cells in Morton's neuroma. RNA bulk sequencing identified 3349 differentially expressed genes between Morton's neuroma and controls. Gene ontology enrichment analysis and weighted gene co-expression network analyses revealed modules specific for host defence and neurogenesis. Deconvolution analysis confirmed higher densities of macrophages and B cells in Morton's neuroma than control samples. Modules associated with defence response, neurogenesis, and muscle system development as well as macrophage cell populations identified by deconvolution correlated with patients' paroxysmal or evoked pain. Of note, we identified a consistently differentially expressed gene signature (MARCO, CD163, STAB1), indicating the presence of a specific M(GC) subset of macrophages. MARCO gene expression correlated with paroxysmal pain. Targeted immunofluorescent analyses confirmed higher densities of intraneural CD163+MARCO+ macrophage subsets in Morton's neuroma. Our findings provide detailed insight into the local molecular signature in the context of human focal nerve injury. There is clear evidence for an ongoing role of the immune system in chronic peripheral neuropathic pain in humans, with macrophages and specifically the M(GC) MARCO+ subset implicated.
AB - Focal nerve injuries are often associated with neuropathic pain. Preclinical research suggests altered neuroimmune signalling underlies such neuropathic pain; however, its cause remains poorly understood in humans. In this multicentre cohort study, we describe the local cellular and molecular signature of neuropathic pain at the lesion site, using Morton's neuroma as a human model system of neuropathic pain (n = 22; 18 women) compared with nerves from participants without nerve injury (n = 11; 4 women). Immunofluorescent staining revealed demyelination and chronic infiltration of immune cells in Morton's neuroma. RNA bulk sequencing identified 3349 differentially expressed genes between Morton's neuroma and controls. Gene ontology enrichment analysis and weighted gene co-expression network analyses revealed modules specific for host defence and neurogenesis. Deconvolution analysis confirmed higher densities of macrophages and B cells in Morton's neuroma than control samples. Modules associated with defence response, neurogenesis, and muscle system development as well as macrophage cell populations identified by deconvolution correlated with patients' paroxysmal or evoked pain. Of note, we identified a consistently differentially expressed gene signature (MARCO, CD163, STAB1), indicating the presence of a specific M(GC) subset of macrophages. MARCO gene expression correlated with paroxysmal pain. Targeted immunofluorescent analyses confirmed higher densities of intraneural CD163+MARCO+ macrophage subsets in Morton's neuroma. Our findings provide detailed insight into the local molecular signature in the context of human focal nerve injury. There is clear evidence for an ongoing role of the immune system in chronic peripheral neuropathic pain in humans, with macrophages and specifically the M(GC) MARCO+ subset implicated.
KW - Immune system
KW - Inflammation
KW - Ligand-receptor analysis
KW - Macrophages
KW - Morton's neuroma
KW - Neuroinflammation
KW - Neuropathic pain
KW - Peripheral nerve injury
KW - RNA sequencing
UR - http://www.scopus.com/inward/record.url?scp=85210733941&partnerID=8YFLogxK
U2 - 10.1097/j.pain.0000000000003472
DO - 10.1097/j.pain.0000000000003472
M3 - Article
AN - SCOPUS:85210733941
SN - 0304-3959
JO - Pain
JF - Pain
ER -