MyD88 Signaling Pathway Is Involved in Renal Fibrosis by Favoring a TH2 Immune Response and Activating Alternative M2 Macrophages

Abstract

Inflammation contributes to the pathogenesis of chronic kidney disease (CKD). Molecules released by the inflamed injured tissue can activate toll-like receptors (TLRs), thereby modulating macrophage and CD4(+) T-cell activity. We propose that in renal fibrogenesis, M2 macrophages are recruited and activated in a T helper subset 2 cell (T(H)2)-prone inflammatory milieu in a MyD88-dependent manner. Mice submitted to unilateral ureteral ligation (UUO) demonstrated an increase in macrophage infiltration with collagen deposition after 7 d. Conversely, TLR2, TLR4 and MyD88 knockout (KO) mice had an improved renal function together with diminished T(H)2 cytokine production and decreased fibrosis formation. Moreover, TLR2, TLR4 and MyD88 KO animals exhibited less M2 macrophage infiltration, namely interleukin (IL)-10(+) and CD206(+) CD11b(high) cells, at 7 d after surgery. We evaluated the role of a T(H)2 cytokine in this context, and observed that the absence of IL-4 was associated with better renal function, decreased IL-13 and TGF-β levels, reduced arginase activity and a decrease in fibrosis formation when compared with IL-12 KO and wild-type (WT) animals. Indeed, the better renal outcomes and the decreased fibrosis formation were restricted to the deficiency of IL-4 in the hematopoietic compartment. Finally, macrophage depletion, rather than the absence of T cells, led to reduced lesions of the glomerular filtration barrier and decreased collagen deposition. These results provide evidence that future therapeutic strategies against renal fibrosis should be accompanied by the modulation of the M1:M2 and T(H)1:T(H)2 balance, as T(H)2 and M2 cells are predictive of fibrosis toward mechanisms that are sensed by innate immune response and triggered in a MyD88-dependent pathway.

Macrophage Trafficking as Key Mediator of Adenine-Induced Kidney Injury

“…In this sense, it is feasible to suggest that the immune cells might be responsible, at least in part, for this injury. The involvement of macrophages infiltration in the renal tissue after an insult was already detected in different works [5, 12]. Several groups have attributed reduced morphologic kidney damage when macrophages were depleted in different experimental models [13, 14].…”

TLR4 mutant mice are protected from renal fibrosis and chronic kidney disease progression

“…Others have shown that, 7 days after unilateral ureteral obstruction (UUO), TLR4 knock-out mice have decreased renal fibrosis of the obstructed kidney and decreased proteinuria in urine collected from the unobstructed kidney in comparison to WT mice (Braga et al. 2012). Similarly, in an adenine-induced tubulointerstitial fibrosis model, TLR4 knock-out mice are protected from interstitial fibrosis and increases in serum creatinine (Correa-Costa et al.…”

“…2010), shifting the balance between M1:M2 macrophage responses (Braga et al. 2012), and fibroblast accumulation (Campbell et al. 2011) during renal fibrogenesis.…”

Recognition of Candida albicans by gingival fibroblasts: The role of TLR2, TLR4/CD14, and MyD88

“…Recently, it was shown that absence of TLR2 decreased the synthesis of type I collagen [30]. These differences among the studies could be explained by the fact that fibroblasts from different anatomic locations differ markedly in their gene expression patterns and show site-specific variations in their transcriptional profiles that seem to be related to their location within the body [31].…”