IL1R8 Deficiency Drives Autoimmunity-Associated Lymphoma Development

Abstract

Chronic inflammation, including that driven by autoimmunity, is associated with the development of B-cell lymphomas. IL1R8 is a regulatory receptor belonging to the IL1R family, which negatively regulates NF-κB activation following stimulation of IL1R or Toll-like receptor family members. IL1R8 deficiency is associated with the development of severe autoimmune lupus-like disease in <i>lpr</i> mice. We herein investigated whether concomitant exacerbated inflammation and autoimmunity caused by the deficiency of IL1R8 could recapitulate autoimmunity-associated lymphomagenesis. We thus monitored B-cell lymphoma development during the aging of IL1R8-deficient <i>lpr</i> mice, observing an increased lymphoid cell expansion that evolved to diffuse large B-cell lymphoma (DLBCL). Molecular and gene-expression analyses showed that the NF-κB pathway was constitutively activated in <i>Il1r8</i> ^-/-/<i>lpr</i> B splenocytes. In human DLBCL, <i>IL1R8</i> had reduced expression compared with normal B cells, and higher <i>IL1R8</i> expression was associated with a better outcome. Thus, <i>IL1R8</i> silencing is associated with increased lymphoproliferation and transformation in the pathogenesis of B-cell lymphomas associated with autoimmunity.