PROJECT SUMMARY/ABSTRACT
Skin sensory neurons are essential for detecting noxious environmental threats and inducing pain and itch.
Neurotransmitters released from skin nerve endings not only mediate these forms of neural sensation but also
drive or regulate inflammatory responses. Several members of the Mas-related G-protein coupled receptor
(MRGPR) family are expressed in sensory neurons and thought to play a crucial role in neuroimmune
interactions. It remains unclear, however, which MRGPRs serve to transduce itch- and inflammation-inducing
signals in atopic dermatitis and other allergic skin diseases. Evidence from our published and preliminary studies
points to mouse MrgprA1 and its human counterpart, MRGPRX2, as the physiologically relevant receptor for
substance P (SP), a neuropeptide with a well-established role in itch and neurogenic inflammation. This finding
challenged the widely held notion that SP stimulated dorsal root ganglion neurons via the neurokinin-1 receptor
and prompted us to investigate whether MrgprA1/MRGPRX2 serves as a key mediator of neuroimmune
interactions and contributes to atopic dermatitis (AD) where itch and inflammation manifest as major
pathophysiologic features. The proposed research will test the hypothesis that MrgprA1/MRGPRX2 expressed
on sensory nerves serves as the SP receptor and plays a crucial role in itch and allergic skin inflammation. For
this investigation, a newly developed mouse model of skin inflammation will be used that closely recapitulates
AD pathophysiology and visualizes peripheral nerve fiber dynamism with exquisite clarity. We will pursue the
following specific aims during the project period: to elucidate the role of MrgprA1 in neuronal SP sensing and
inflammation-associated itch (Aim 1); to determine the contribution of Mrgpr-expressing sensory neurons and
MrgprA1 signaling to shaping the skin immune microenvironment and driving allergic skin inflammation (Aim 2);
and to assess the potential of antagonizing MrgprA1 action and MrgprA1+ nerve dynamism for AD treatment
(Aim 3). The proposed research tests novel ideas and seeks to close knowledge gaps in neuroscience,
immunology, and skin biology. If successful, this research project will establish new molecular mechanisms by
which neuronal Mrgpr signaling mediates neuroimmune interactions and contributes to AD and other allergic
skin diseases. This knowledge will translate into effective clinical strategies for the treatment of itch and skin
inflammation.