Lupus-prone NZM2328 mice exhibit enhanced UV-induced myeloid cell recruitment and activation in a type I interferon dependent manner

Mitra P Maz; Alayka L Reddy; Celine C Berthier; Lam C Tsoi; Deborah J Colesa; Sonya J Wolf; Hong Shi; Shannon N Loftus; Rezvan Moallemian; Rachael Bogle; Matthias Kretzler; Chaim O Jacob; Johann E Gudjonsson; J Michelle Kahlenberg

doi:10.1016/j.jaut.2024.103296

Lupus-prone NZM2328 mice exhibit enhanced UV-induced myeloid cell recruitment and activation in a type I interferon dependent manner

J Autoimmun. 2024 Sep 5:149:103296. doi: 10.1016/j.jaut.2024.103296. Online ahead of print.

Authors

Affiliations

¹ Div. of Rheumatology, Dept. of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI, USA; Immunology Graduate Program, University of Michigan, Ann Arbor, MI, USA.
² Div. of Rheumatology, Dept. of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
³ Div. of Nephrology, Dept. of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
⁵ Div. of Rheumatology, Dept. of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Immunology Graduate Program, University of Michigan, Ann Arbor, MI, USA.
⁶ University of Southern California Keck School of Medicine, Los Angeles, CA, USA.
⁷ Div. of Rheumatology, Dept. of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.
⁸ Div. of Rheumatology, Dept. of Internal Medicine, University of Michigan, Ann Arbor, MI, USA; Department of Dermatology, University of Michigan, Ann Arbor, MI, USA. Electronic address: mkahlenb@med.umich.edu.

PMID: 39241536
DOI: 10.1016/j.jaut.2024.103296

Abstract

Though the exact causes of systemic lupus erythematosus (SLE) remain unknown, exposure to ultraviolet (UV) light is one of the few well-known triggers of cutaneous inflammation in SLE. However, the precise cell types which contribute to the early cutaneous inflammatory response in lupus, and the ways that UV dosing and interferons modulate these findings, have not been thoroughly dissected. Here, we explore these questions using the NZM2328 spontaneous murine model of lupus. In addition, we use iNZM mice, which share the NZM2328 background but harbor a whole-body knockout of the type I interferon (IFN) receptor, and wild-type BALB/c mice. 10-13-week-old female mice of each strain were treated with acute (300 mJ/cm² x1), chronic (100 mJ/cm² daily x5 days), or no UVB, and skin was harvested and processed for bulk RNA sequencing and flow cytometry. We identify that inflammatory pathways and gene signatures related to myeloid cells - namely neutrophils and monocyte-derived dendritic cells - are a shared feature of the acute and chronic UVB response in NZM skin greater than iNZM and wild-type skin. We also verify recruitment and activation of these cells by flow cytometry in both acutely and chronically irradiated NZM and WT mice and demonstrate that these processes are dependent on type I IFN signaling. Taken together, these data indicate a skewed IFN-driven inflammatory response to both acute and chronic UVB exposure in lupus-prone skin dominated by myeloid cells, suggesting both the importance of type I IFNs and myeloid cells as therapeutic targets for photosensitive patients and highlighting the risks of even moderate UV exposure in this patient population.

Keywords: Interferon; Myeloid cells; Systemic lupus; Ultraviolet light.