Author ORCID Identifier
https://orcid.org/0000-0003-2277-5205
Date of Award
2026
Document Type
Thesis (Ph.D.)
Department or Program
Microbiology and Immunology
First Advisor
Dr. Sladjana Skopelja-Gardner
Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by multi-organ inflammation, with lupus nephritis (LN) representing a major cause of morbidity. Ultraviolet (UV) light is a well-established environmental trigger of SLE disease flares; however, the mechanisms linking cutaneous inflammation to renal pathology remain poorly understood. In this work, I investigated the role of neutrophils as mediators of inter-organ communication within a UV-triggered skin–kidney axis.
In this work, I demonstrate that UV-induced skin injury promotes neutrophil trafficking to the kidney and drives distinct tissue responses depending on disease context. To do this, I utilized in vivo mouse models, transcriptomic analyses, and spatial profiling of human LN tissue. In healthy mice, UV exposure induces renal neutrophils to upregulate pro-angiogenic transcriptional programs and promote endothelial activation and tissue remodeling through interactions such as CD177–PECAM1 signaling. In contrast, in lupus-prone MRL/lpr mice, UV exposure drives neutrophil-dependent activation of profibrotic pathways, including TGF-β and Wnt signaling. Spatial transcriptomic analysis of human LN biopsies reveals that neutrophil-rich regions are associated with both tissue remodeling and pro-fibrotic signatures and are enriched in patients with concurrent skin involvement.
Further characterization of neutrophils in LN demonstrates significant cellular heterogeneity, including normal-density (NDN), low-density (LDN), and CXCR4+ subsets with distinct functional roles. LDN-enriched regions are associated with inflammatory and oxidative stress pathways, whereas NDN-enriched regions are linked to tissue remodeling and injury responses. Both subsets exhibit elevated type I interferon (IFN-I) signaling, which acts as a key regulator of neutrophil phenotype and function. Disruption of IFN-I signaling attenuates UV-induced pro-angiogenic neutrophil responses.
Collectively, these findings identify neutrophils as central mediators of a UV-driven skin–kidney axis and demonstrate that their functional heterogeneity and regulation by IFN-I signaling determine context-dependent outcomes ranging from adaptive tissue repair to pathogenic fibrosis in a LN environment.
Original Citation
Angelique Cortez, Lindsay K. Mendyka, Alecia Roy, Joshua J. Skydel, Lais Osmani, Paola Garcia, Elizabeth C. Nowak, Akshaya Balasubramanian, Noelle Kosarek, Fred W. Kolling, Owen M. Wilkins, Olivia F. Brooker, Chinaza Nnam, Jason Pettus, William F.C. Rigby, Vivekanand Tiwari, Christopher M. Burns, Lucas A Salas, Michelle Petri, Andrea Fava, Sladjana Skopelja-Gardner. A skin–kidney neutrophil axis links UV exposure to renal angiogenesis and tissue remodeling in healthy and lupus kidneys, Journal of Immunology (Accepted for publication)
Recommended Citation
Cortez, Angelique, "Defining Neutrophil-Mediated Skin-to-Kidney Crosstalk in Lupus Nephritis" (2026). Dartmouth College Ph.D Dissertations. 505.
https://digitalcommons.dartmouth.edu/dissertations/505
