Role of 5-HT1A and 5-HT3 receptors in serotonergic activation of sensory neurons in relation to itch and pain behavior in the rat

Dan Domocos, Tudor Selescu, Laura Cristina Ceafalan,  Mirela Iodi Carstens, Earl Carstens, Alexandru Babes

Abstract

Serotonin (5-hydroxytryptamine, 5-HT) released by platelets, mast cells, and immunocytes is a potent inflammatory mediator which modulates pain and itch sensing in the peripheral nervous system. The serotonergic receptors expressed by primary afferent neurons involved in these sensory functions are not fully identified and appear to be to a large extent species dependent. Moreover, the mechanisms through which 5-HT receptor activation is coupled to changes in neuronal excitability have not been completely revealed. Using a combination of in vitro (calcium and voltage imaging and patch-clamp) and in vivo behavioral methods, we used both male and female Wistar rats to provide evidence for the involvement of two 5-HT receptor subtypes, 5-HT1A and 5-HT3, in mediating the sustained and transient effects, respectively, of 5-HT on rat primary afferent neurons involved in pain and itch processing. In addition, our results are consistent with a model in which sustained serotonergic responses triggered via the 5-HT1A receptor are due to closure of background potassium channels, followed by membrane depolarization and action potentials, during which the activation of voltage-gated calcium channels leads to calcium entry. Our results may provide a better understanding of mammalian serotonergic itch signaling.

https://onlinelibrary.wiley.com/doi/full/10.1002/jnr.24633

A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity

Abstract

The novel Coronavirus SARS-CoV-2 causes a respiratory illness called COVID-19 leading to a pandemic. An effective preventive vaccine against this virus is urgently needed. As the most critical step during infection, SARS CoV-2 uses its Spike protein receptor-binding domain (S- RBD) to engage with the host cell receptor angiotensin converting enzyme 2 (ACE2)1,2. Here we showed that a recombinant vaccine comprising residues 319-545 of the S-RBD could induce a potent functional antibody response in the immunized mice, rabbits and non-human primates (Macaca mulatta) as early as 7 or 14 days after a single dose injection. The sera from the immunized animals blocked RBD binding to ACE2 expressed on the cell surface and neutralized the infection by SARS-CoV-2 pseudovirus and live SARS-CoV-2 in vitro. Importantly, the vaccination also provided protection in non-human primates from SARS-CoV-2 challenge in vivo. The elevated RBD-specific antibodies were also found in the sera from patients with COVID-19. Several immune pathways and CD4 T lymphocytes were implicated in the induction of the vaccine antibody response. Our finding highlights the importance of the RBD domain in the SARS-CoV-2 vaccine design and provides the rationale for the development of a protective vaccine through the induction of antibody against the RBD domain.

Periostin Activation of Integrin Receptors on Sensory Neurons Induces Allergic Itch

Santosh K. Mishra,1,2,3,4,9,* Joshua J. Wheeler,1,2 Saumitra Pitake,1 Huiping Ding,5 Changyu Jiang,7 Tomoki Fukuyama,1 Judy S. Paps,8 Patrick Ralph,1 Jacob Coyne,1 Michelle Parkington,1 Jennifer DeBrecht,1 Lauren C. Ehrhardt-Humbert,1 Glenn P. Cruse,1,2 Wolfgang Ba ̈ umer,1,6 Ru-Rong Ji,7 Mei-Chuan Ko,5 and Thierry Olivry2,8
1Department of Molecular Biomedical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA 2Comparative Medicine Institute, North Carolina State University, Raleigh, NC, USA

3The WM Keck Behavioral Center, North Carolina State University, Raleigh, NC, USA
4Program in Genetics, North Carolina State University, Raleigh, NC, USA
5Department of Physiology and Pharmacology, Wake Forest School of Medicine, Winston-Salem, NC, USA
6Institute of Pharmacology and Toxicology, Department of Veterinary Medicine, Freie Universita ̈ t Berlin, Berlin, Germany 7Duke University, Durham, NC, USA
8Department of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA 9Lead Contact
*Correspondence: skmishra@ncsu.edu

SUMMARY

Chronic allergic itch is a common symptom affecting millions of people and animals, but its pathogenesis is not fully explained. Herein, we show that periostin, abundantly expressed in the skin of patients with atopic dermatitis (AD), induces itch in mice, dogs, and monkeys. We identify the integrin aVb3 expressed on a subset of sensory neurons as the periostin receptor. Using pharmacological and ge- netic approaches, we inhibited the function of neuronal integrin aVb3, which significantly reduces periostin-induced itch in mice. Furthermore, we show that the cytokine TSLP, the application of AD- causing MC903 (calcipotriol), and house dust mites all induce periostin secretion. Finally, we establish that the JAK/STAT pathway is a key regulator of periostin secretion in keratinocytes. Altogether, our results identify a TSLP-periostin reciprocal activation loop that links the skin to the spinal cord via periph- eral sensory neurons, and we characterize the non- canonical functional role of an integrin in itch.