The Neuroimmune Interplay in Joint Pain: The Role of Macrophages

Abstract

Chronic pain associated with joint disorders, such as rheumatoid arthritis (RA), osteoarthritis (OA) and implant aseptic loosening (AL), is a highly debilitating symptom that impacts mobility and quality of life in affected patients. The neuroimmune crosstalk has been demonstrated to play a critical role in the onset and establishment of chronic pain conditions. Immune cells release cytokines and immune mediators that can activate and sensitize nociceptors evoking pain, through interaction with receptors in the sensory nerve terminals. On the other hand, sensory and sympathetic nerve fibers release neurotransmitters that bind to their specific receptor expressed on surface of immune cells, initiating an immunomodulatory role. Macrophages have been shown to be key players in the neuroimmune crosstalk. Moreover, macrophages constitute the dominant immune cell population in RA, OA and AL. Importantly, the targeting of macrophages can result in anti-nociceptive effects in chronic pain conditions. Therefore, the aim of this review is to discuss the nature and impact of the interaction between the inflammatory response and nerve fibers in these joint disorders regarding the genesis and maintenance of pain. The role of macrophages is highlighted. The alteration in the joint innervation pattern and the inflammatory response are also described. Additionally, the immunomodulatory role of sensory and sympathetic neurotransmitters is revised.

Targeting Nuclear Receptors for Chronic Inflammatory Pain: A Potential Alternative

“…1,3 While a variety of immune mediators and cell types may play a role in inflammationmediated pain, macrophages are often recognized as having an important function in the development of chronic pain. 1,4 Macrophages are essential for tissue repair processes that occur following nerve damage. Activated macrophages release inflammatory mediators including interleukin-1β (IL-1β) that can alter the functioning of local fibroblasts and promote tissue damage.…”

“…Particularly, a variety of inflammatory mediators (both local to the nerve injury and within the central nervous system; CNS) can activate nociceptors and initiate pain signaling. 1 Oftentimes, chronic activity of immune mediators leads to increased pain symptoms as well as increased injury and cellular turnover. In many cases, short-term therapies including steroids and pain relievers can alleviate these symptoms, but the pain and inflammation will often return, leading to the use of stronger analgesics including opioids.…”

“…The neuro-immune pathway plays a clear role in the development of chronic pain. Particularly, a variety of inflammatory mediators (both local to the nerve injury and within the central nervous system; CNS) can activate nociceptors and initiate pain signaling . Oftentimes, chronic activity of immune mediators leads to increased pain symptoms as well as increased injury and cellular turnover.…”

Six macrophage-associated genes in synovium constitute a novel diagnostic signature for osteoarthritis

“…Under pathological conditions, the balance of proinflammatory and anti-inflammatory driven by M1/M2 macrophages is broken, resulting in immunogenic damage to osteoarticular tissues and contributing to the resting pain symptom ( 12 ). In addition, accumulation of synovial macrophages also contributes to osteoarthritis joint pain through various mechanisms, such as pain sensitization ( 13 ), high expression of the neurotrophin nerve growth factor ( 14 ), and neuroimmune cross talk ( 15 ). Taken together, synovial macrophages are important mediators of immune activation and related pathologies in OA, but their transcriptional changes associated with macrophage activation have not been fully clarified.…”

Neuroimmune Crosstalk in Rheumatoid Arthritis

“…In addition, PNS interacts with immune cells in the gut, lungs, skin, and other peripheral organs to form neuroimmune cell units that initiate inflammatory states and maintain tissue homeostasis. In addition, inflammatory mediators such as nerve growth factor, C-C Motif Chemokine Ligand, and pro-inflammatory cytokines, can also interact with receptors in joint nociceptors then inducing their activation and sensitization in RA [ 6 ]. Neuron-derived neuropeptides and neurotransmitters that neurons can produce modulate the function and response of immune cells, while immune cells can also produce inflammatory factors that increase neuronal activity.…”