Quaternary Ammonium Compound Disinfectants Reduce Lupus-Associated Splenomegaly by Targeting Neutrophil Migration and T-Cell Fate.

Leila Abdelhamid,Qinghui Mu,Ryan P Seguin,Brianna Swartwout,Xavier Cabana-Puig,Terry C Hrubec,Prerna Das,Libin Xu,Mital Lavani,Xin M Luo,Sarah Lowen,Caroline N Jones,Maryam Moarefian,Kristin Eden

doi:10.3389/fimmu.2020.575179

Abstract

Hypersensitivity reactions and immune dysregulation have been reported with the use of quaternary ammonium compound disinfectants (QACs). We hypothesized that QAC exposure would exacerbate autoimmunity associated with systemic lupus erythematosus (lupus). Surprisingly, however, we found that compared to QAC-free mice, ambient exposure of lupus-prone mice to QACs led to smaller spleens with no change in circulating autoantibodies or the severity of glomerulonephritis. This suggests that QACs may have immunosuppressive effects on lupus. Using a microfluidic device, we showed that ambient exposure to QACs reduced directional migration of bone marrow-derived neutrophils toward an inflammatory chemoattractant ex vivo. Consistent with this, we found decreased infiltration of neutrophils into the spleen. While bone marrow-derived neutrophils appeared to exhibit a pro-inflammatory profile, upregulated expression of PD-L1 was observed on neutrophils that infiltrated the spleen, which in turn interacted with PD-1 on T cells and modulated their fate. Specifically, QAC exposure hindered activation of splenic T cells and increased apoptosis of effector T-cell populations. Collectively, these results suggest that ambient QAC exposure decreases lupus-associated splenomegaly likely through neutrophil-mediated toning of T-cell activation and/or apoptosis. However, our findings also indicate that even ambient exposure could alter immune cell phenotypes, functions, and their fate. Further investigations on how QACs affect immunity under steady-state conditions are warranted.

Highlights

Systemic lupus erythematosus (SLE or lupus) is a complex multisystem autoimmune disorder with diverse clinical manifestations [1,2,3], with enlargement of lymphoid organs as one of the first symptoms [4,5,6]
Concerned that the pro-inflammatory neutrophils in QACexposed mice would lead to kidney dysfunction associated with lupus [37, 55, 56], we investigated the severity of glomerulonephritis
A significant percentage of splenic CD3+ cells from quaternary ammonium compound disinfectants (QACs)-exposed mice were CD62L+CD44− naïve T cells (Figure S6F), resulting in a significant increase of the ratio of naïve vs. effector T cells (Figure S6G). These results indicate reduced splenic T-cell expansion and activation in the ambient QAC-exposed environment that may have resulted from increased PD-L1:PD-1 interaction between neutrophils and T cells

Summary

Introduction

Systemic lupus erythematosus (SLE or lupus) is a complex multisystem autoimmune disorder with diverse clinical manifestations [1,2,3], with enlargement of lymphoid organs as one of the first symptoms [4,5,6]. Aside from genetic factors, this heterogeneity is strongly influenced by environmental factors [13, 14] that could drive the progression of SLE in susceptible individuals and shape treatment outcomes. To understand the possible effects of QACs on innate immunity, we investigated how QACs affected murine macrophages in vitro. Effective macrophage responses are required for clearance of autoantigens; and impaired macrophages responses could contribute to the development of autoimmune conditions [22]. These findings raised the question of whether QAC exposure would cause immune dysregulation and affect systemic autoimmunity such as lupus.

Methods

Results

Conclusion