Neuroimmune modulation of pain and regenerative pain medicine

Abstract

Regenerative pain medicine, which seeks to harness the body's own reparative capacity, is rapidly emerging as a field within pain medicine and orthopedics. It is increasingly appreciated that common analgesic mechanisms for these treatments depend on neuroimmune modulation. In this Review, we discuss recent progress in mechanistic understanding of nociceptive sensitization in chronic pain with a focus on neuroimmune modulation. We also examine the spectrum of regenerative outcomes, including preclinical and clinical outcomes. We further distinguish the analgesic mechanisms of regenerative therapies from those of cellular replacement, creating a conceptual and mechanistic framework to evaluate future research on regenerative medicine.

Figure 1. Pathogenesis of neuropathic pain and arthritic pain via gene regulation in DRG neurons and neuroinflammation in the spinal cord.

Lower left: Epigenetic regulation in DRG neurons in peripheral sensitization after nerve injury. In primary sensory neurons, MBD1 epigenetically suppresses expression of μ-opiod receptor and potassium channel subtype Kv1.2 (encoded by Kcna2). Kcna2 expression is also silenced by long noncoding RNA (lncRNA). Activity of G9a in DRG neurons increases following nerve injury, resulting in epigenetic silencing of more than 40 potassium channel subtypes. Voltage-gated calcium channel subunits α2δ-1 and α2δ-2, the molecular targets of gabapentin, are regulated by the miR-183 cluster. Right: Spinal cord microglia activation in chronic pain. Nerve injury and joint injury induce upregulation of MMP-9 and CSF-1 in DRG neurons. MMP-9 and CSF-1 undergo axonal transport to the spinal cord dorsal horn. Upon release, MMP-9 and CSF-1 induce microglia activation (e.g., p38 phosphorylation) and microgliosis (proliferation and morphological changes) in the ipsilateral spinal cord, leading to the development of chronic pain. Lower right: Spinal cord neuroinflammation in central sensitization and chronic pain. Upon activation, microglia produce and release IL-1β, which induces central sensitization and chronic pain via both presynaptic and postsynaptic regulations, leading to increased EPSCs and decreased IPSCs. IL-1β also modulates the activation of microglia and astrocytes in the spinal cord. Delayed but persistent MMP-2 production in astrocytes contributes to late-phase neuropathic pain. Both MMP-9 and MMP-2 are involved in regulating the cleavage and activation of IL-1β. Inhibition of MMP-9 and MMP-2 by TIMP-1 and TIMP-2 blocks neuropathic pain.

Figure 2. Preclinical models of cellular and cell-free exosome therapies for chronic pain.

(i) Single systemic or local injection of BMSCs can reverse mechanical allodynia by in vivo immune interactions and activation of monocytes. (ii) Intrathecally injected BMSCs migrate to meninges of injured DRG neurons and spinal cord dorsal horn via a CXCL12/CXCR4 homing mechanism. TGF-β1 secretion by BMSCs confers potent long-term pain relief by activation of the neuronal TGF-β receptor (TGF-βR). (iii) Intrathecal injection of exosomes derived from human umbilical cord mesenchymal cells can serve as cell-free therapy for neuropathic pain. (iv) Transplantation of embryonic cortical GABAergic interneuron precursors from the medial ganglionic eminence (MGE) into the spinal cord leads to the development of inhibitory neurons. Furthermore, these GABAergic neurons integrate into spinal nociceptive circuits, mediating pain relief by release of GABA that acts on host-transplant inhibitory synaptic circuits.

Figure 3. Clinically used blood-derived and cell-derived pain therapies and their mechanisms of action via production of therapeutic mediators.

(A) PRP contains (a) α-granule–derived growth factors such as PDGF, TGF-β, and HGF, as well as TIMP-1 and TIMP-2 and (b) monocyte-derived factors including TGF-β, FGF, and IGF. ACS provides factors including IL-1 receptor antagonist (IL-1Rα), IL-4, IL-10, and TGF-β. MSCs have been found in clinical treatments to alter macrophage phenotypes, leading to direct and indirect production of IL-10 and TGF-β. MSCs also produce TSG-6 to inhibit inflammation and promote wound healing. Blood- and cell-derived therapies could also contain exosomes.(B) Common therapeutic mediators and mechanisms of action include (a) control of neuroinflammation, (b) tissue repair, and (c) pro-resolution processes. Notably, PRP, ACS, and MSCs may also contain or produce SPMs that produce multiple beneficial effects. ACS, autologous conditioned serum; MSC, mesenchymal stromal cells; PRP, platelet-rich plasma; SPM, specialized pro-resolving mediators.