The Role of Toll-Like Receptor 2 in Inflammation and Fibrosis during Progressive Renal Injury

Abstract

Tissue fibrosis and chronic inflammation are common causes of progressive organ damage, including progressive renal disease, leading to loss of physiological functions. Recently, it was shown that Toll-like receptor 2 (TLR2) is expressed in the kidney and activated by endogenous danger signals. The expression and function of TLR2 during renal fibrosis and chronic inflammation has however not yet been elucidated. Therefore, we studied TLR2 expression in human and murine progressive renal diseases and explored its role by inducing obstructive nephropathy in TLR2−/− or TLR2+/+ mice. We found that TLR2 is markedly upregulated on tubular and tubulointerstitial cells in patients with chronic renal injury. In mice with obstructive nephropathy, renal injury was associated with a marked upregulation and change in distribution of TLR2 and upregulation of murine TLR2 danger ligands Gp96, biglycan, and HMGB1. Notably, TLR2 enhanced inflammation as reflected by a significantly reduced influx of neutrophils and production of chemokines and TGF-β in kidneys of TLR2−/− mice compared with TLR2+/+ animals. Although, the obstructed kidneys of TLR2−/− mice had less interstitial myofibroblasts in the later phase of obstructive nephropathy, tubular injury and renal matrix accumulation was similar in both mouse strains. Together, these data demonstrate that TLR2 can initiate renal inflammation during progressive renal injury and that the absence of TLR2 does not affect the development of chronic renal injury and fibrosis.

Small leucine-rich proteoglycans orchestrate receptor crosstalk during inflammation

“…In sepsis, decorin alone mimicks the effects of LPS by enhancing plasma and tissue levels of proinflammatory TNFα, IL-12 Several authors have described the coincidence of biglycan overexpression with enhanced inflammation and severe tissue injury. [54][55][56] The correlation between enhanced abundance of biglycan and reduction of organ function in various sterile inflammatory renal diseases has been particularly well documented. 8,19,[55][56][57][58] Upregulation of biglycan in aortic stenosis, characterized by lipid accumulation and inflammation, 59 results in enhanced synthesis of phospholipid transfer protein via stimulation of TLR2.…”

“…[54][55][56] The correlation between enhanced abundance of biglycan and reduction of organ function in various sterile inflammatory renal diseases has been particularly well documented. 8,19,[55][56][57][58] Upregulation of biglycan in aortic stenosis, characterized by lipid accumulation and inflammation, 59 results in enhanced synthesis of phospholipid transfer protein via stimulation of TLR2. 60 Furthermore, higher levels of biglycan in cardiac transplant coronary arteriopathy, 58 severe ocular surface disease 61 and in adipose tissue 62 suggest a role for biglycan in the perpetuation of inflammation.…”

CD14 Signaling Reciprocally Controls Collagen Deposition and Turnover to Regulate the Development of Lyme Arthritis

“…[45][46][47] In renal injury and cystic fibrosis, excessive TLR2 signaling induces several fibrotic genes. [45][46][47][48] The absence of CD14 on macrophages results in a 50-fold increase in B. burgdorferi-stimulated transcription of tlr2 and protracted surface expression of protein, which, in turn, is partly responsible for greater production of proinflammatory cytokines. The ability of macrophages to trigger apoptosis in myofibroblasts also may depend on CD14 expression.…”

Participação de diferentes subtipos de macrófagos e a contribuição do ácido úrico solúvel, dos receptores TLR2 e TLR4 e das moléculas MyD88 e NLRP3 para o desenvolvimento da fibrose renal.

“…O remodelamento da MEC e o estresse celular liberam moléculas que ativam respostas inflamatórias via receptores do sistema imune inato. Vários grupos demonstraram a importância de receptores do tipo Toll em DRC, onde estes receptores são ativados por produtos relacionados à deposição de componentes da MEC (63,65,105). Por outro lado, dados anteriores mostram que a deficiência em TLR2 e TLR4 faz com que animais sejam mais protegidos da fibrose (63)(64)(65)105), porém, até agora, pouco se sabe como que a ativação desses receptores culmina no processo de fibrogênese.…”

“…Vários grupos demonstraram a importância de receptores do tipo Toll em DRC, onde estes receptores são ativados por produtos relacionados à deposição de componentes da MEC (63,65,105). Por outro lado, dados anteriores mostram que a deficiência em TLR2 e TLR4 faz com que animais sejam mais protegidos da fibrose (63)(64)(65)105), porém, até agora, pouco se sabe como que a ativação desses receptores culmina no processo de fibrogênese. Além disso, já foi proposto que citocinas de padrão Th2 estão implicadas na formação de fibrose em diferentes modelos de doenças crônicas (50,52,106).…”