# Regulation of wound healing pathways by NLRP10 in cutaneous Leishmaniasis

> **NIH NIH R21** · CEDARS-SINAI MEDICAL CENTER · 2023 · $404,140

## Abstract

PROJECT SUMMARY
Cutaneous leishmaniasis results in skin ulcerations that can take months to years to resolve resulting in
significant morbidity. Pharmacologic interventions to aid in healing of these lesions would lessen morbidity, but
the mechanisms that regulate the repair of Leishmania lesions are not well understood. In addition, there has
been little investigation into the role of innate immune Nucleotide-Binding Domain and Leucine Rich Repeat
Receptor (NLR) family members in regulating wound healing. Using a mouse model of cutaneous leishmaniasis,
we have found a novel role for the NLR family member NLRP10 in healing of infected wounds, as mice that lack
NLRP10 develop larger lesions that fail to heal compared to wild-type mice. While most studies of the NLR family
of pattern recognitions receptors have identified roles for these receptors in hematopoietic cells, in this model
NLRP10 regulates wound healing from a non-hematopoietic cell population. Importantly, while the lesions in
NLPRP10-deficient mice were larger than those of wild-type mice, this was not due to a failure to control the
parasite, as there was no difference in parasite burden between the groups. In contrast, healing of sterile wounds
was intact in NLRP10-deficient mice, suggesting the requirement for NLRP10 is specific to the presence of
pathogenic microorganisms in the wound. In this proposal, we aim to identify the mechanism by which NLRP10
regulates wound repair in cutaneous leishmaniasis. We have found that NLRP10-deficient fibroblasts have
blunted proliferation. While evaluating the reason for this failure, we identified that these fibroblasts arrested their
proliferation at the G0/G1 phase of the cell cycle. We also found NLRP10-deficient fibroblasts displayed
increased markers of senescence, with elevated β-galactosidase staining and increased p16 and p21
expression. NLRP10-deficient fibroblasts also showed morphologic features of senescence and had increased
secretion of pro-inflammatory cytokines and chemokines, consistent with these cells having a senescence-
associated secretory phenotype (SASP). We propose that NLRP10 acts within fibroblasts in cutaneous
leishmaniasis lesions to mitigate senescence and in doing so aids in the wound repair response. Utilizing the
p16-3MR mouse model, which will allow us to both identify and selectively kill senescent cells, we will be able to
define the contribution of senescence to wound repair in cutaneous leishmaniasis and determine how NLRP10
regulates this process. We will determine the factors in L. major lesions that drive fibroblast senescence in the
absence of NLRP10. We will further define the influence of NLRP10 on the SASP and determine the factor
required for repair of cutaneous leishmaniasis wounds. Our studies will define the role of NLRP10 in regulating
senescence pathways and identify novel therapeutic targets to accelerate cutaneous wound healing in a variety
of pathologies.

## Key facts

- **NIH application ID:** 10783649
- **Project number:** 1R21AR083485-01
- **Recipient organization:** CEDARS-SINAI MEDICAL CENTER
- **Principal Investigator:** Fayyaz S. Sutterwala
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $404,140
- **Award type:** 1
- **Project period:** 2023-09-18 → 2025-09-17

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10783649

## Citation

> US National Institutes of Health, RePORTER application 10783649, Regulation of wound healing pathways by NLRP10 in cutaneous Leishmaniasis (1R21AR083485-01). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10783649. Licensed CC0.

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