Editorial: [Microglia and Tissue Macrophages in Pain]

Darian MohseninJessica YuZhonghui GuanXiaobing Yu^*

• University of California, San Francisco, San Francisco, United States

Following injury or diseases of the somatosensory nervous system, neuropathic pain is usually long-lasting and manifested with either negative symptoms such as loss of sensation or positive symptoms characterized by allodynia or hyperalgesia in a neuroanatomically plausible distribution 1 . Neuropathic pain can be further divided into peripheral and central pathology. Common peripheral neuropathic pain includes trigeminal neuralgia, peripheral nerve injury-induced chronic neuropathic pain, postherpetic neuralgia, etc, whereas central neuropathic pain can coexist with lesions of the central nervous system such as traumatic brain and spinal cord injury, stroke and multiple sclerosis (MS) 2 . With prevalence varying from 6.9% to 10% 3 , neuropathic pain profoundly impacts human well-being, both physically and psychologically, with substantial health care costs.To date, managing neuropathic pain remains an unmet clinical challenge.Over the past decades, there has been an exponential growth of both preclinical and clinical research on neuropathic pain. Insights of pain processing mechanisms have come from studying peripheral nerve injury induced neuropathic pain models 4 , and neuroimmune interactions are increasingly recognized as an essential driver of neuropathic pain 5 . It is well known that spinal microglia contribute to the induction and maintenance of neuropathic pain following peripheral nerve injury [6][7][8][9] . Moreover, microglia also play a critical role in inducing sensitization of the dorsal horn pain processing circuitry by releasing pro-inflammatory mediators, such as interleukin-1β (IL-1b), tumor necrosis factor-alpha (TNF-ɑ), and prostaglandin E2 (PGE2) 6 . Notably, the contribution of microglia signaling to nerve-injury induced neuropathic pain is sexually dimorphic 10 . Targeting spinal microglial cells to reduce injury-induced mechanical hypersensitivity is only effective in male mice and has little impact in female mice. On the other hand, a reciprocal interaction between sensory neurons and macrophages contributes to both acute 11 and persistent injury-induced neuropathic and inflammatory pain, in both sexes [12][13][14] . A recent nociceptor-immune interactome study further predicts that macrophages are the strongest immune cell interactors of sensory neurons in the context of tissue injury 15 .Through preclinical studies, many potential analgesic targets implicated in neuropathic pain in rodents have been identified. Unfortunately, most molecular candidates have failed to translate to the clinic. It has been increasingly debated among pain researchers and clinicians whether preclinical animal models reliably recapitulate human therapeutic responses, given interspecies biological differences 16,17 and unreliable outcome measures 18 .In this special issue of Frontiers in Immunology, Dhir et al. set out to identify knowledge gaps in the research of investigating spinal microglia changes in murine models of neuropathic pain. Their comprehensive review found that changes in microglia and pain behavior were only acutely recorded up to 2 weeks after nerve injury in most of the 258 peer-reviewed articles. The findings highlight the need to study chronic pain models. Moreover, the authors call for the inclusion of both sexes in future chronic pain studies.Aiming for developing novel nonopioid pain treatment, Ruan et al. focused on ozone therapy in chronic constriction injury of the sciatic nerve animals. The authors demonstrated that Ozone significantly alleviated neuropathic pain by promoting macrophage efferocytosis and suppressing neuroinflammation through the AMPK/Gas6-MerTK/SOCS3 signaling pathway. Although Ozone therapy has been proposed as an adjunct pain treatment for its antimicrobial, anti-inflammatory properties 19 , its efficacy and long-term safety remains to be determined.With etiology poorly understood, neuropathic pain commonly occurs in 20% to 50% of MS patients 20,21 Taken together, this special issue aims to addressing the gaps in chronic pain research, emphasizing longitudinal studies and inclusive experimental designs. The findings further underscore the complementary roles of microglia and macrophages in the development and resolution of neuropathic pain. Integrating insights from both compartments will hold promise for translating neuroimmune findings into the clinic and improving pain management.