Rubicon promotes rather than restricts murine lupus and is not required for LC3-associated phagocytosis.

Rachael A Gordon,Richard Cattley,Anne Davidson,Sheldon I Bastacky,Anthony Marinov,Chirag Raparia,Mark J Shlomchik,William Hawse,Kevin M Nickerson,Jeremy S Tilstra,Christina Giannouli,Allison M Campbell

doi:10.1172/jci.insight.155537

Abstract

NADPH oxidase deficiency exacerbates lupus in murine models and patients, but the mechanisms remain unknown. It is hypothesized that NADPH oxidase suppresses autoimmunity by facilitating dead cell clearance via LC3-associated phagocytosis (LAP). The absence of LAP reportedly causes an autoinflammatory syndrome in aged, nonautoimmune mice. Prior work implicated cytochrome b-245, β polypeptide (CYBB), a component of the NADPH oxidase complex, and the RUN and cysteine-rich domain-containing Beclin 1–interacting protein (RUBICON) as requisite for LAP. To test the hypothesis that NADPH oxidase deficiency exacerbates lupus via a defect in LAP, we deleted Rubicon in the B6.Sle1.Yaa and MRL.Faslpr lupus mouse models. Under this hypothesis, RUBICON deficiency should phenocopy NADPH oxidase deficiency, as both work in the same pathway. However, we observed the opposite — RUBICON deficiency resulted in reduced mortality, renal disease, and autoantibody titers to RNA-associated autoantigens. Given that our data contradict the published role for LAP in autoimmunity, we assessed whether CYBB and RUBICON are requisite for LAP. We found that LAP is not dependent on either of these 2 pathways. To our knowledge, our data reveal RUBICON as a novel regulator of SLE, possibly by a B cell–intrinsic mechanism, but do not support a role for LAP in lupus.

Highlights

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by loss of tolerance, rampant immune activation, and end-organ damage [1]
To determine whether Cybb deficiency exacerbates SLE by prevention of dead cell clearance due to a defect in LC3-associated phagocytosis (LAP), we genetically deleted another requisite component for LAP, Rubicon, in the B6.Sle1.Yaa and MRL.Faslpr lupus models
To determine whether CYBB and RUBICON act in the same pathway (i.e. LAP), we analyzed Cybb and Rubicon single and double knockout mice in the setting of lupus

Summary

Introduction

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by loss of tolerance, rampant immune activation, and end-organ damage [1]. While the sources of autoantigens in lupus remain enigmatic, a failure to adequately dispose of dead cells and resulting debris by macrophages is a leading possibility [2]. There are several lines of evidence that link dead cell clearance pathways to the development of systemic autoimmunity. [7,8,9,10,11,12,13] Taken together, these studies emphasize that inadequate clearance of dead cells can result in an immune response to self and subsequent end-organ damage

Methods

Results

Conclusion