THE FUEL OF CHRONIC PAIN: Mitochondria and neuro-immune interactions

Pain is an important warning signal that normally disappears when the stimuli that caused it disappear. However, pain often persists for months or even years after the original rigger has disappeared. This chronic pain is debilitating and affects ~20% of the world population. Chronic inflammatory and bone pain are common causes of chronic pain and affect millions of people worldwide. These types of pain are caused by diseases such as osteoarthritis, rheumatoid arthritis, lupus, psoriasis, ankylosing spondylitis, bone cancer or fibrous dysplasia. Existing therapies are not effective in treating chronic inflammatory and bone pain, and often cause severe side effects. Recent evidence shows that immune cells and neuronal mitochondrial disturbances play an important role in chronic pain. Nevertheless, there is still an incomplete understanding of how these aspects contribute to the development of chronic inflammatory and bone pain. Therefore, in this thesis, we examined the role of mitochondrial regulation and neuroimmune interactions in chronic pain, with a particular focus on the transition between acute and chronic inflammatory pain and chronic bone pain. In this thesis, we show that inflammation-induced mitochondrial and metabolic disturbances in sensory neurons predispose to failing pain resolution pathways. Moreover, targeting specific elements of these disturbances such as the redox balance and or the mitochondrial protein ATPSc-KMT in sensory neurons were sufficient to restore resolution of inflammatory pain and prevent chronic pain. We identified that the increased oxidative stress associated with the observed disturbed redox balance results in the activation of the NLRP3 inflammasome pathway in sensory neurons. Inhibiting the NLRP3 inflammasome pathway prevents not only the transition from acute to chronic inflammatory pain, but also reduces osteoarthritis pain. Interestingly, in male mice with osteoarthritis pain, NLPR3 inflammasome inhibition had longer-lasting analgesic effects than in females. Moreover, NLPR3 inflammasome inhibition decreased the population of inflammatory macrophages in the dorsal root ganglia (DRG) only in males. These data indicate that NLRP3 inflammasome activation contributes to osteoarthritis pain in a sex dependent manner, while also highlighting the importance of neuro-immune interactions in chronic pain. We further add to the evidence that the immune system plays a key role in pain regulation, by showing that macrophages contribute to the development of cancer bone pain, another type of bone pain which etiology is not fully understood. However, in contrast to osteoarthritis pain, DRG and spinal cord macrophages do not contribute to the maintenance of cancer bone pain. Future research has to identify in which tissues these macrophages contribute to bone cancer pain. Lastly, we showed that the inhibitory immune receptor LAIR-1 is required to resolve from inflammatory pain, likely through T cells mediated regulation Thus, we identified a previously unknown role for LAIR-1 in the regulation of inflammatory pain. Overall, the studies described in the thesis unveil how mitochondrial regulation and neuro-immune interactions contribute to chronic pain development.