Malcangio Lab research
Research at the Malcangio lab focuses on plasticity of the first pain synapse.
My laboratory has a long-standing interest in the biology of spinal cord mechanisms underlying chronic pain as the strength of the first pain synapse formed by primary sensory neurones and dorsal horn neurones in the spinal cord is plastic and modifiable. In the development and establishment of chronic pain, significant plastic changes occur at both pre- and post- synaptic sites of the sensory synapse with significant contribution of non-neuronal-mediated mechanisms. My current work explores several approaches to target neuropathic and arthritis pain, with particular emphasis on the involvement of microglia and macrophages through proteases and chemokines pathways.
In the last decade, we have devoted our research interest to the role played by non-neuronal cells in modulating the activity of the first pain synapse. We have identified a pathway which includes the cysteine protease cathepsin S and the chemokine fractalkine. The lysosomal cathespin S is expressed by microglia in the spinal cord whereas fractalkine is found in neurons as a transmembrane protein. Under conditions of neuropathic pain associated with neural injury, the neuronal expression of fractalkine stays unaltered whilst cathepsin S-expressing microglial cells increase in number in the dorsal horn (Figure 1).
Cathepsin S (CatS) staining in the dorsal horn of naïve and sciatic nerve injured (Seltzer model) rats. In both naïve and nerve injured dorsal horns CatS is found in microglial cells (Iba-1marker). Resting microglia turn from a ramified appearance in naïve cords to activated microglia (increased size of cell body and thickening of proximal processes) after injury
The microglial cells contribute to the sensitization of the first pain synapse by
releasing cathepsin S in ATP/P2X7-mediated fashion. Extracellular CatS is
responsible for the liberation of the chemotactic domain of fractalkine
(Fig.2). Soluble fractalkine activates its microglial receptor CX3CR1 to
stimulate p38 MAPK phosphorylation and promote the release of pro-nociceptive
mediators (Fig.2) which ultimately active neurons.
The cathepsin S and fractalkine pathway in neuron-microglia communication in the spinal cord. Activated microglial cells release cathepsin S (CatS) (1) Which then liberates soluble F KN (sF KN) fron neurons (2) sF KN through the interaction with the CX3CR1 receptor on microglia (3) activates the p38 MAPK pathway (4) and promotes the release inflammatory mediators (5) which activates neurons (6) and result in pain (7). We propose that cathepsin S inhibition constitutes a novel therapeutic approach for the treatment of chronic pain.
The current research of my laboratory focuses on the role that proteases, cytokines and chemokines play in neuronal-microglial communication in the establishment and maintenance of chronic pain. We use clinically relevant models of pain originating peripherally (peripheral nerve injury,diabetic neuropathy, chemotherapy-induced neuropathic pain, collagen-induced arthritis, bone cancer pain) and centrally (Alzheimer’s disease, experimental autoimmune encephalytis). We are supported by the Wellcome Trust, the Arthritis Research UK, Medical Research Council and European Commission FP7 grants.