Resident fibroblasts in the kidney: a major driver of fibrosis and inflammation

Abstract

Background: Chronic kidney disease (CKD) is a leading cause of end stage renal disease (ESRD) and cardiovascular morbidity and mortality worldwide, resulting in a growing social and economic burden. The prevalence and burden of CKD is anticipated to further increase over the next decades as a result of aging.

Main body of abstract: In the pathogenesis of CKD, irrespective of the etiology, resident fibroblasts are key players and have been demonstrated to play crucial roles for disease initiation and progression. In response to injury, resident fibroblasts transdifferentiate into myofibroblasts that express alpha smooth muscle actin (αSMA) and have an increased capacity to produce large amounts of extracellular matrix (ECM) proteins, leading to renal fibrosis. In addition to this fundamental role of fibroblasts as drivers for renal fibrosis, growing amounts of evidence have shown that resident fibroblasts are also actively involved in initiating and promoting inflammation during kidney injury. During the myofibroblastic transition described above, resident fibroblasts activate NF-κB signaling and produce pro-inflammatory cytokines and chemokines, promoting inflammation. Furthermore, under aging milieu, resident fibroblasts transdifferentiate into several distinct phenotypic fibroblasts, including CXCL13/CCL19-producing fibroblasts, retinoic acid-producing fibroblasts, and follicular dendritic cells, in response to injury and orchestrate tertiary lymphoid tissue (TLT) formation, which results in uncontrolled aberrant inflammation and retards tissue repair. Anti-inflammatory agents can improve myofibroblastic transdifferentiation and abolish TLT formation, suggesting that targeting these inflammatory fibroblasts can potentially ameliorate kidney disease.

Short conclusion: Beyond its conventional role as an executor of fibrosis, resident fibroblasts display more pro-inflammatory phenotypes and contribute actively to driving inflammation during kidney injury.

Keywords: CXCL13; Chronic kidney disease; Erythropoietin; Fibroblast; Heterogeneity; Inflammation; Myofibroblast; Tertiary lymphoid tissue.

Fig. 1

Tertiary lymphoid tissues in aged injured mouse kidney. Tertiary lymphoid tissues are mainly composed of T cells and B cells, some of which are proliferating. p75NTR-positive fibroblasts extend their projections and form a structural backbone within TLTs. a green: CD3ε, red: B220. b green: p75NTR, red: Ki67. Scale bar (a, b) 50 μm

Fig. 2

The distinct injury response in young and aged mice. Aged mice, but not young mice, developed multiple tertiary lymphoid tissues (TLTs) in the kidney after acute kidney injury (AKI). TLTs sustain and amplify inflammation and retard regeneration, resulting a poor renal outcome in aged mice

Fig. 3

Fibroblasts have two jobs during CKD: fibrosis and inflammation. Resident fibroblasts critically contribute to fibrosis and the persistence of inflammation in the injured kidney [3]. Upon injury, resident fibroblasts transdifferentiate into myofibroblasts, which produce a large amount of ECM protein and pro-inflammatory cytokines/chemokines, at the cost of EPO production. Moreover, in the aging milieu, resident fibroblasts also transdifferentiate into several distinct phenotypic fibroblasts, which orchestrate TLT formation. In response to injury, resident fibroblasts differentiate into RALDH-positive fibroblasts, which induce transdifferentiation of other fibroblasts into p75NTR-positive fibroblasts with three phenotypes, which include CXCL13- and CCL19-producing fibroblasts. In the later phase of TLT formation, some of these p75NTR-positive fibroblasts lose this expression and mature into CD21/CXCL13-positive FDCs