Innate-Immune Sensing by Nociceptors

Understanding the molecular mechanisms of nociception has recently grown impressively. Nociception is mediated by mechanical, chemical, or microbial stimuli that evoke unpleasant feelings, alerting the host of the risk of tissue damage. Such diverse arrays of noxious stimuli trigger various escape reactions, usually altering immune homeostasis. Notably, nociceptors can recognize cytokines or pathogens via sensory molecules or innate immune receptors, participating in immune responses. Accumulating evidence suggests that activated nociceptors produce various humoral factors that affect the immune system and act like endocrine/paracrine signals. Thus, understanding the interplay between the nociceptive and immune systems may open new avenues for the development of an interdisciplinary research field, hereinafter referred to as “senso-immunology.”

Innate immune cells, particularly macrophages, recognize pathogens via toll-like receptors (TLRs) and produce pro-inflammatory cytokines. Pathogen-mediated direct activation of innate immune cells is considered a pivotal reaction at the forefront of host-pathogen interactions. Since pain neurons are abundantly distributed in various organs such as skin, lung, and intestine, they are also considered the first cells exposed to pathogens. Interestingly, recent reports have indicated that pain neurons directly recognize pathogens like innate immune cells. For instance, gram-negative bacterial component lipopolysaccharide (LPS) can be detected by TLR4 and TRPA1 in pain neurons, leading to the production of calcitonin gene-related peptide (CGRP) and calcium influx induction. TLR3 and TLR7 are also expressed on pain neurons and are activated by double stranded RNA and miR-let-7b, respectively, leading to the nociceptor activation. S. aureus, the most major gram-positive pathogen in humans, can induce acute pain in mice; however, such pain levels are not altered by knockout of key molecules involved in pro-inflammatory cytokine production, such as Myd88. These findings suggest that S. aureus-induced pain may not be evoked by pro-inflammatory mediators. Notably, S. aureus-derived pore-forming peptide named α-hemolysin directly activates pain neurons, leading to the induction of action potential. Besides bacterial infections, it is well known that fungal infections also cause pain. For instance, C. albicans-derived β-glucan reportedly stimulates nociceptors depending on its receptor Dectin-1. It is well known that cough reflex is evoked by pain neurons innervating the lungs. Very recently, it has been reported that Mycobacterium tuberculosis (Mtb) glycolipid Sulfolipid-1 (SL-1) functions as a nociceptive molecule, and SL-1 activates both mouse and human pain neurons. Strikingly, SL-1-producing Mtb strains induce coughing in guinea pigs. When the tissue becomes inflamed, immune cells produce a variety of cytokines. It is well known that TNF-α and IL-1β, innate immune cell-related cytokines, act directly on pain neurons and enhance neuronal excitability. Recently, it has been reported that not only TNF-α and IL-1β, but also type 2 cytokines, such as IL-4, enhance neuronal responsiveness. Notably, IL-4 receptor IL-4Rα was detected in pain neurons, and pain neuron-specific deletion of IL-4Rα reduces chronic itching. These findings above indicate that cytokines are involved in controlling itching as well as pain, and that the direct action of cytokines or pathogens on pain neurons is critical in the development of nociception.

This Research Topic will highlight infectious and inflammatory diseases originating from the skin, lung, pancreas, bone, and gut, discussing the possibility that the innate-immune sensing by nociceptors (pain neurons and various nociceptive ion channels) and its impact to these conditions. We welcome the submission of Original Research and Review Articles, which cover, but are not limited to, the following topics:

1. Bacteria sensing by the nociceptive system

2. Cytokine sensing by the nociceptive system

3. Paracrine functions of nociceptive system in response to inflammation

4. Immune phenotypes of pain neuron or nociceptive ion channel null mice