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\begin{document}

\title{Local inflammation enables a basophil-neuronal circuITCH in atopic
dermatitis}



\author[1]{Anna Ehlers}%
\author[2]{Celia López Sanz}%
\author[2]{Rodrigo Jimenéz-Saiz}%
\affil[1]{Universitair Medisch Centrum Utrecht}%
\affil[2]{Hospital Universitario de la Princesa}%


\vspace{-1em}



  
  \date{June 17, 2024}


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\selectlanguage{english}
\begin{abstract}
Acute itch flares in atopic dermatitis via the LTC4-CysLTR2 pathway.%
\end{abstract}%



\sloppy


\textbf{Title} : Local inflammation enables a
basophil-neuronal\emph{circuITCH} in atopic dermatitis

\textbf{Authors:} Celia L\selectlanguage{ngerman}ópez-Sanz\textsuperscript{1}, Rodrigo
Jimenéz-Saiz\textsuperscript{1-4}, Anna M Ehlers\textsuperscript{5,6}

\textsuperscript{1}Department of Immunology, Instituto de Investigación
Sanitaria Hospital Universitario de La Princesa (IIS-IP), Madrid, Spain

\textsuperscript{2}Department of Immunology and Oncology, Centro
Nacional de Biotecnología (CNB)-CSIC, Madrid, Spain

\textsuperscript{3}Faculty of Experimental Sciences, Universidad
Francisco de Vitoria (UFV), Madrid, Spain

\textsuperscript{4}McMaster Immunology Research Centre, Department of
Medicine, McMaster University, Hamilton, Ontario, Canada

\textsuperscript{5}Center for Translational Immunology, University
Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

\textsuperscript{6}Department of Dermatology/Allergology, University
Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands

\textbf{Correspondence to:}

Anna M Ehlers

Center for Translational Immunology

Heidelberglaan 100,

3584 CX Utrecht, The Netherlands

a.m.ehlers-2@umcutrecht.nl

\textbf{Keywords:} basophils; allergic inflammation; leukotriene C;
neuroimmunology; atopic dermatitis; itch;

\textbf{Abbreviations:} AD, atopic dermatitis; CCL, C-C chemokine
ligand; CCR; C-C chemokine receptor; CysLTR, Cysteinyl leukotriene
receptor; DT, diphtheria toxin; HR, histamine receptor; LT, leukotriene;
MCs, mast cells; OVA, ovalbumin.

\textbf{Main text}

Allergic inflammation is often the result of a dysregulated Th2 immune
response, IgE production, and the release of allergic mediators such as
histamine or leukotrienes (LTs) by basophils and mast cells (MCs).
Allergic diseases can manifest as acute allergic reactions
(anaphylaxis), or as chronic allergic inflammation in chronic urticaria,
allergic rhinitis, allergic asthma, and atopic dermatitis
(AD).\textsuperscript{1} Common allergic symptoms such as sneezing,
airway mucus secretion, and chronic itch are caused by interactions
between immune cells and sensory neurons in the inflamed
tissue.\textsuperscript{2, 3}

The MC-neuronal axis is involved in chronic itch experienced by AD
patients. Stimulated MCs release, among other mediators, histamine,
which directly activates pruriceptor sensory neurons via histamine
receptors (HR) and elicit itch.\textsuperscript{3} However, it remains
unclear how acute itch flares are triggered in certain subpopulations of
AD patients. Recently, Wang \emph{et} \emph{al.} observed that acute
itch flares were associated with increased serum specific IgE in
patients with moderate to severe AD.\textsuperscript{4} They showed
MC-independent acute itch flares in an AD-like disease murine model
sensitized to ovalbumin (OVA) and deficient in MCs
(Sash\textsuperscript{-/-} mice) upon OVA challenge. Additionally, they
performed basophil depletion experiments using anti-CD200R in wild type
mice, and diphtheria toxin (DT) in Bas-TRECK mice, which exclusively
express the DT receptor on basophils. Altogether, Wang \emph{et al} .
uncovered the requirement of basophils for acute itch flares, and its
redundancy for chronic itch behavior and specific IgE production in AD.

The critical role of basophils in acute itch flares was restricted to
chronic AD-like skin disease because acute itch flares in OVA-sensitized
wild type mice were MC- but not basophil-dependent. These data were
strengthened by passive immunization experiments with OVA-specific IgE,
where acute itch flares were only basophil-dependent in the
AD-associated inflammatory disease model.\textsuperscript{4} This
apparent riddle was explained by the scarce dermis infiltration of
circulating basophils without previous inflammation. In contrast,
a\emph{chronically-inflamed environment} promoted basophil recruitment
that enabled them to migrate through the dermis to interact with sensory
neurons. This interaction caused acute pruritus via the LTC4-Cysteinyl
leukotriene receptor (CysLTR) 2 pathway (\textbf{Fig. 1}
).\textsuperscript{4}

LTs are well-known lipid mediators involved in several pro-inflammatory
responses via CysLTR1 or CyLTR2, which are expressed on murine and human
dorsal root ganglia neurons.\textsuperscript{4} Besides its involvement
in AD-associated acute itch flares, the LTC4-CysLTR2 pathway was also
required for MC activation and eosinophil-dependent skin fibrosis in an
OVA-induced AD murine model.\textsuperscript{5} Interestingly, recent
studies have demonstrated the relevance of the LTC4-CysLTR2 axis for
acute and chronic itch behavior in chronic inflammation. On the other
hand, this axis was redundant for acute (\emph{Alternaria} -induced
itch) or non-inflammatory itch (dry skin induced
itch).\textsuperscript{5}

Chronic tissue inflammation promotes basophil infiltration via C-C
chemokine receptor (CCR) 1, 2 and 3 that bind to chemoattractants such
as C-C chemokine ligand (CCL) 2, 5 and 11. CCR-CCL interactions
upregulate \selectlanguage{greek}α- \selectlanguage{english}and \selectlanguage{ngerman}ß-integrin in basophils and other leukocytes. These
integrins interact with vascular cell adhesion molecules, fibronectin or
intercellular adhesion molecules 1-3 of the vascular endothelium for
diapedesis.\textsuperscript{6} In addition, the release of
damage-associated molecular patterns, or alarmins, such as thymic
stromal lymphopoietin, IL-33 and IL-25, empowers basophil recruitment
into the inflamed tissue. Also, allergens such as Der f 2
from\emph{Dermatophagoides farinae} have been reported to induce, and
even enhance, chemokine-induced basophil migration.\textsuperscript{7}
It has been shown by 2-photon imaging of (murine) skin lesions and
airway histology of fatal asthma cases that, alike MCs,
tissue-infiltrated basophils can locate near to sensory
neurons,\textsuperscript{4, 8}which likely favors a basophil-neuronal
interplay.

Basophils were long thought to be redundant with MCs in atopy, until
recently, that their role has been recognized in different phases of
allergic pathology,\textsuperscript{1} including sensitization and
anaphylaxis.\textsuperscript{9} The newly identified basophil-dependent
LTC4-CysLTR2 pathway may contribute to chronic allergic diseases other
than AD. For example, allergic rhinitis and allergic asthma are
characterized by recurrent (on-season) allergen exposure, which may
trigger continuous basophil tissue infiltration (\textbf{Fig. 1} ).
Also, it would be intriguing to examine whether subclinical doses of
food allergens, which can be constantly ingested without symptomatology,
can promote basophil migration to the oro-gastrointestinal tract. This
may be particularly relevant for oral immunotherapy, characterized by
the administration of steadily increasing doses of allergen over months,
and even years, for desensitization. Thus, targeting these putative
basophil-neuronal interactions during oral immunotherapy may improve
patient´s safety and compliance by reducing adverse side events.

In conclusion, the work by Wang \emph{et} \emph{al.} adds insight on
basophil-neuronal interactions to the brand new and rapidly growing
field of neuroimmunology. Understanding the fundamental mechanisms and
immunological principles that govern effector cell (MC/basophil)-neuron
communication in the landscape of chronic allergic inflammatory diseases
is a prerequisite for the identification of novel therapeutic targets in
allergy.

\textbf{Conflict of interest} : The authors have no conflict of interest
to declare.

\textbf{Financial support} : RJS´s laboratory acknowledges the support
received by the Severo Ochoa Program (AEI/SEV-2017-0712), FSE/FEDER
through the Instituto de Salud Carlos III (ISCIII; CP20/00043), The
Nutricia Research Foundation (NRF-2021-13), New Frontiers in Research
Fund (NFRFE-2019-00083), and SEAIC (BECA20A9).

\textbf{Authorship} : The authors approved the final version of the
manuscript as submitted and agreed to be accountable for all aspects of
the work.

\textbf{Acknowledgements} : The authors want to thank Dr. Anna Globinska
for graphical abstract design. CLS and AME drafted the manuscript and
RJS provided critical feedback and revisions. All authors approved the
final version for submission.

\textbf{References}

1. Miyake, K. and H. Karasuyama, \emph{Emerging roles of basophils in
allergic inflammation.} Allergol Int, 2017. \textbf{66} (3): p. 382-91.

2. Voisin, T., A. Bouvier, and I.M. Chiu, \emph{Neuro-immune
interactions in allergic diseases: Novel targets for therapeutics.} Int
Immunol, 2017. \textbf{29} (6): p. 247-61.

3. Kabata, H. and D. Artis, \emph{Neuro-immune crosstalk and allergic
inflammation.} J Clin Invest, 2019. \textbf{129} (4): p. 1475-82.

4. Wang, F., et al., \emph{A basophil-neuronal axis promotes itch.}Cell,
2021. \textbf{184} (2): p. 422-40.e17.

5. Voisin, T., et al., \emph{The CysLT2R receptor mediates leukotriene
C4-driven acute and chronic itch.} Proc Natl Acad Sci U S A,
2021.\textbf{118} (13): p. e2022087118.

6. Korosec, P., et al., \emph{Basophils, high-affinity IgE receptors,
and CCL2 in human anaphylaxis.} J Allergy Clin Immunol,
2017.\textbf{140} (3): p. 750-8.e15.

7. Suzukawa, M., et al., \selectlanguage{greek}\emph{IgE- and FcεRI-mediated migration of
human basophils.}\selectlanguage{english} Int Immunol, 2005. \textbf{17} (9): p. 1249-55.

8. Koshino, T., et al., \emph{Identification of basophils by
immunohistochemistry in the airways of post-mortem cases of fatal
asthma.} Clin Exp Allergy, 1993. \textbf{23} (11): p. 919-25.

9. Kashiwakura, J.-I., et al., \emph{The basophil-IL-4-mast cell axis is
required for food allergy.} Allergy, 2019. \textbf{74} (10): p. 1992-6.

\textbf{Figure Legend}

\textbf{Figure 1} . Acute itch flares in AD patients are associated with
increased levels of specific IgE (top left side). While chronic itch
behavior is dependent on MC-neuronal communication, acute itch relies on
basophil-neuronal interaction via the LTC4-CysLTR2 pathway (bottom), as
demonstrated with different AD-like disease murine models sensitized to
OVA (top middle). The underlying requirement for this pathway seems to
be chronic inflammation, which can also occur in other allergic
diseases. A continuous local inflammation may promote basophil tissue
infiltration, where they can reside in proximity to sensory neurons
favoring a basophil-neuronal interplay (right side). Bas, basophils.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/2021-06-21-Figure-1/2021-06-21-Figure-1}

\end{center}
\end{figure}

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