AGING INDUCES NLRP3 INFLAMMASOME DEPENDENT ADIPOSE B CELL EXPANSION TO IMPAIR METABOLIC HOMEOSTASIS

Christina Camell,Vishwa Deep Dixit

doi:10.1093/geroni/igz038.397

Abstract

Visceral adiposity in elderly is associated with alterations in adipose tissue immune cells leading to inflammation and metabolic dysfunction. The Nlrp3 inflammasome is a critical regulator of macrophage activation, inflammation, and immunometabolism in visceral adipose tissue during aging; however, the potential contribution of adipose tissue B cells is unexplored. Here, we show that aging expands adipose-resident B cells and fat-associated lymphoid clusters (FALCs) in visceral white adipose tissue of female mice. Adipose tissue B cells exhibit a memory-like B cell profile similar to the phenotype of aged B cells that are increased in spleen of old mice. Mechanistically, the age-induced FALC formation and adipose B cell expansion, but not B cell transcriptional program, is dependent on the Nlrp3 inflammasome. Furthermore, B cell depletion in aged mice improves insulin sensitivity and metabolic capacity of adipose tissue. These data reveal that inhibiting Nlrp3-dependent B cell accumulation can be targeted to reverse metabolic impairment in aging adipose tissue.

Highlights

Increased visceral adiposity that is seen in aged individuals is accompanied by a decreased ability of adipose tissue to maintain homeostatic functions (Kennedy et al, 2014; Stenholm et al, 2008)
We have previously shown that aging is associated with reduction in visceral adipose tissue macrophage subsets which lack M1 or M2 polarization, but display senescent-like gene expression signatures that is in part dependent on the Nlrp[3] inflammasome (Camell et al, 2017)
We found that ablation of the Nlrp[3] inflammasome in aging protects against adipose tissue-resident B cell expansion and Fat-associated lymphoid clusters (FALCs) development, without altering the inflammatory transcriptional profile of resident adipose B cells

Summary

Introduction

Increased visceral adiposity that is seen in aged individuals is accompanied by a decreased ability of adipose tissue to maintain homeostatic functions (Kennedy et al, 2014; Stenholm et al, 2008). White adipose tissue is highly heterogeneous containing defined microenvironment niches in which tissue resident macrophages have distinct roles that facilitate tissue maintenance. Niches such as crown-like-structures (CLS), in which dying adipocytes are cleared by macrophages (Cinti et al, 2005; Martinez-Santibanez and Lumeng, 2014), and sympathetic nerve fibers, in which nerve-associated macrophages regulate local access to catecholamines that stimulate lipolysis (Bartness et al, 2014; Camell et al, 2017; Pirzgalska et al, 2017), have been implicated in metabolic pathogenesis during aging and obesity. The contribution of FALCs and FALC-resident cells to agerelated metabolic dysregulation remains unknown

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