TRPA1 channels are early sensors of gram-negative bacterial endotoxins

Resumen del trabajo presentado al 12th World Congress on Inflammation, Symposium 18: Ion Channels and Inflammation-Sponsored by IRN-Canada; celebrado en Boston (US) del 8 al 12 de agosto de 2015.-- et al.TRPA1 are calcium permeable, non-selective cation channels expressed in sensory endings of somatic and visceral nociceptors and many non-neuronal cells, including fibroblasts, endothelial and glial cells. These ion channels are critically involved in the biological response to physical stimuli (temperature and pressure) and natural and synthetic environmental irritants, including many electrophiles, reactive oxygen species and endogenous inflammatory mediators produced following tissue damage. Abnormal activation of TRPA1 has been linked to the pathogenesis of neuropathic pain and itch, and a number of systemic inflammatory diseases, including atopic dermatitis, irritable bowel syndrome and asthma. Gram-negative bacterial infections are accompanied by inflammation and somatic or visceral pain. These symptoms are generally attributed to sensitization of nociceptors by inflammatory mediators released by immune cells. Nociceptor sensitization during inflammation by lipopolysaccharide (LPS), a toxic byproduct of gramnegative bacterial lysis, is thought to occur through activation of pattern-recognition receptors, in particular the Toll-like-receptor 4 (TLR4) signaling pathway. Using a combination of experimental techniques, including electrophysiological recordings and cellular calcium imaging, we found that LPS exerts fast (seconds) activation of mouse somatic and visceral nociceptors. These actions were mediated by opening of TRPA1 channels leading to neuronal depolarization, firing of action potentials and rapid elevation of intracellular calcium levels. Human TRPA1 channels showed a similar sensitivity to LPS. LPS, injected intradermally, produced a rapid (minutes) inflammatory response that was accompanied by pain and acute vascular reactions, including neurogenic inflammation and CGRP release (measured by enzyme immunoassay). These responses were severely blunted in TRPA1 KO mice and developed independently of TLR4 activation. Moreover, the capacity of various forms of LPS, purified from different pathogens, to activate TRPA1 in vitro correlated with their ability to induce inflammatory responses in vivo. In summary, we identified TRPA1 channels as key molecular determinants of rapid LPS effects on sensory neurons and their terminals, leading to acute neurogenic inflammation and pain. These results suggest that TRPA1 channels may play a previously unrecognized role in the first line of immune defense against microbial pathogens. Pharmacological targeting of TPA1 channels could represent a novel therapeutic avenue for treatment of complications derived from gram negative bacterial infections, including septic shock.Financial support provided by project SAF2013-45608-R of MINECO.Peer reviewe