Divergent roles of immune cells and their mediators in pain

Abstract

Chronic pain is a major debilitating condition that is difficult to treat. Although chronic pain may appear to be a disorder of the nervous system, crucial roles for immune cells and their mediators have been identified as important contributors in various types of pain. This review focuses on how the immune system regulates pain and discusses the emerging roles of immune cells in the initiation or maintenance of chronic pain. We highlight which immune cells infiltrate damaged nerves, the dorsal root ganglia, spinal cord and tissues around free nerve endings and discuss through which mechanisms they control pain. Finally we discuss emerging roles of the immune system in resolving pain and how the immune system contributes to the transition from acute to chronic pain. We propose that targeting some of these immune processes may provide novel therapeutic opportunities for the treatment of chronic pain.

Fig. 1

Overview of the role of immune cells and their mediators at different stages of pain (A) Time course of chronic pain induced by inflammation or damage visualizing the different stages of pain: (i) initiation, (ii)maintenance and (iii) resolution. (B and C) Schematic overview of the different types of immune cells and mediators modulating pain at different sites and during the different stages (i–iii) of pain shown in (A). (B) During inflammation or tissue damage, resident and immune cells recruited to the inflamed or damaged site secrete inflammatory mediators that act on peripheral nerves innervating the affected tissue. (C) Similarly, different immune cells migrate to the spinal cord and/or the dorsal root ganglia to modulate pain sensitivity during the different phases of pain. ACPA: anti-citrullinated protein antibody; ASIC, acid-sensing ion channel; ATP: adenosine triphosphate; CCL2: chemokine (C-C motif) ligand 2; CRF: corticotropin-releasing factor; CX3CL1: chemokine (C-X3-C motif) ligand 1; Fcγ1: Fcγ type 1 receptor; GPCR: Gprotein-coupled receptor; NGF: nerve growth factor; PD1/NPD1: protectin D1/neuroprotectin D1; ROS: reactive oxygen species.

Fig. 2

Macrophages infiltrate the DRG in a model of OA (A) Unilateral intra-articular monosodium iodoacetate (MIA) injections in rats significantly increased the number of CD68⁺ macrophages in the lumbar DRG compared with the contralateral knee or vehicle injected rats at 4 weeks after injections (n = 6). (B) Exemplar images of the DRGs innervating the affected knee (ipsi) or the contral lateral knee (contra). Scale bar is 50 μm. Data are presented as mean and s.e.m. ***P < 0.001: statistical analyses were performed by two-way analysis of variance with the Bonferroni post hoc test.