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decreasing the levels of genes responsible for proliferation and survival. These findings suggest that SLPI
contributes to neutrophil production because it can regulate signal transduction downstream of G-CSFR in
myeloid cells and improve their proliferation.

[25]
Another SLPI-dependent mechanism involved in neutropenia relates to the UPR response . Correlative
evidence links the severity of neutropenia, the expression of SLPI in myeloid cells from neutropenia
patients, and the ability to trigger UPR stress pathways. These studies reported significantly lower levels of
SLPI in patients with SCN compared to individuals with milder CyN . Moreover, higher expression of
[25]
SLPI in CyN has been suggested to provide protection against the UPR response. The combined
suppression of SLPI and the transduction of ELANE mutant S126L in myeloid cells led to an elevation of the
expression of several genes that are responsible for the induction of the UPR pathways. Taken together,
these findings suggest that the magnitude of ELANE-triggered UPR response might be regulated by a
natural inhibitor of NE - SLPI.

CONCLUSION
Gene editing technology has expanded our mechanistic understanding of how distinct ELANE mutations
yield different outcomes, but has also potentially offered a universal approach for the treatment of ELANE
neutropenia. In addition, previous experimental NE-based mouse models had limited clinical predictive
power. The HSPCs models may offer a potential solution to this problem and provide a tool to further
dissect the pathogenesis of congenital neutropenia. Finally, NE inhibitors need to be better explored in the
context of neutropenia. A better understanding of the mechanisms underlying congenital neutropenia could
help the development of alternative treatment options.

DECLARATIONS
Acknowledgements
NE structure shown in the graphical abstract was created using the PyMOL Molecular Graphics System,
Version 2.5 Schrödinger, LLC.

Authors’ contributions
Made substantial contributions to the conception and design of the study: Mazur A, Skrzeczynska-
Moncznik J, Majewski P, Cichy J
Drafted the manuscript: Mazur A, Skrzeczynska-Moncznik J, Majewski P, Cichy J
Edited the manuscript: Cichy J
All authors approved the submitted version of the article.

Availability of data and materials
Not applicable.

Financial support and sponsorship
This paper was supported by European Cooperation in Science and Technology (COST) Action CA18233,
“European Network for Innovative Diagnosis and treatment of Chronic Neutropenias, EuNet
INNOCHRON”.

Conflicts of interest
All authors declared that there are no conflicts of interest.