# Interleukin-36 upregulates type-I interferon responses in systemic lupus erythematosus by promoting the accumulation of self-nucleic acids

## TL;DR

This study shows that IL-36 increases type-I interferon responses in lupus by causing monocyte apoptosis and reducing self-nucleic acid clearance.

## Contribution

The novel finding is that IL-36 promotes self-nucleic acid accumulation in SLE through monocyte apoptosis and RNAse downregulation.

## Key findings

- IL-36 treatment upregulates IRF7-driven type-I IFN pathways in classical monocytes.
- IL-36 downregulates RNAse genes and increases monocyte apoptosis, leading to self-nucleic acid accumulation.
- IL-36 activity correlates with IRF7 activity in SLE monocytes (r=0.35, P=0.02).

## Abstract

Several studies have reported an up-regulation of interleukin (IL)-36 in the serum of patients with systemic lupus erythematosus (SLE). Here, we sought to define the mechanisms whereby IL-36 may contribute to the over-activation of type I Interferon (IFN) responses observed in SLE.

We carried out single-cell (sc)RNA-seq in healthy peripheral blood mononuclear cells treated with IL-36 (n=5 donors). We compared the genes and transcriptional networks that were induced by IL-36 with those that were upregulated in a published SLE scRNA-seq dataset (n=33 cases and 11 controls). In follow-up studies, we validated the effects of IL-36 on monocytes by real-time PCR (n=9 donors) and flow-cytometry (n=6).

Classical monocytes were the immune population most affected by IL-36 treatment (n=203 Differentially Expressed Genes). In these cells, IL-36 upregulated transcriptional networks (regulons) driven by IRF7, a key activator of type I IFN responses. A similar upregulation of IRF7 regulons was observed in the monocytes of SLE cases, where measurements of IL-36 and IRF7 activity were significantly correlated (r=0.35, P = 0.02). Experimental follow-up studies in human monocytes showed that IL-36 downregulates multiple RNAse genes (RNASE1, RNASE6, RNASET2). IL-36 treatment of monocytes also increased the percentage of apoptotic cells (45% vs 37% in untreated cells; P = 0.001), which are a critical source of self-nucleic acids.

We find that IL-36 promotes monocyte apoptosis while downregulating self-nucleic acid clearance. Thus, IL-36 contributes to the accumulation of self-nucleic acids, a key driver of type I IFN responses in SLE.