MyD88 signaling pathway is involved in renal fibrosis by favoring a TH2 immune response and activating alternative M2 macrophages

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 a...

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Published in:	Molecular medicine (Cambridge, Mass.) Vol. 18; no. 8; pp. 1231 - 1239
Main Authors:	Braga, Tarcio Teodoro, Correa-Costa, Matheus, Guise, Yuri Felipe Souza, Castoldi, Angela, de Oliveira, Cassiano Donizetti, Hyane, Meire Ioshie, Cenedeze, Marcos Antonio, Teixeira, Simone Aparecida, Muscara, Marcelo Nicolas, Perez, Katia Regina, Cuccovia, Iolanda Midea, Pacheco-Silva, Alvaro, Gonçalves, Giselle Martins, Camara, Niels Olsen Saraiva
Format:	Journal Article
Language:	English
Published:	England BioMed Central 24-10-2012 ScholarOne
Subjects:	Animals Antigens Apoptosis Chronic illnesses Collagen Creatinine Cytokines Cytokines - metabolism Fibrosis Flow cytometry Hematopoiesis Immunity - immunology Interleukin-12 - metabolism Interleukin-4 - deficiency Kidney - immunology Kidney - pathology Kidney - physiopathology Kidney Diseases - immunology Kidney Diseases - pathology Kidney Diseases - physiopathology Kidney Function Tests Kidneys Ligation Macrophage Activation - immunology Macrophages - immunology Macrophages - pathology Male Mice Mice, Inbred C57BL Mice, Knockout Myeloid Differentiation Factor 88 - metabolism Proteins Reagents Signal Transduction - immunology Th2 Cells - immunology Toll-Like Receptor 2 - metabolism Toll-Like Receptor 4 - metabolism Tumor necrosis factor-TNF Ureter - pathology Ureteral Obstruction - complications Ureteral Obstruction - immunology Ureteral Obstruction - pathology Denmark Brazil United States > US
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1076-1551 1528-3658
DOI:	10.2119/molmed.2012.00131