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 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.
Laboratory of Transplantation Immunobiology, Department of Immunology, Institute of Biomedical Sciences IV, University of São Paulo, São Paulo, Brazil.
Tarcio Teodoro
TT
Braga
Matheus
M
Correa-Costa
Yuri Felipe Souza
YF
Guise
Angela
A
Castoldi
Cassiano Donizetti
CD
de Oliveira
Meire Ioshie
MI
Hyane
Marcos Antonio
MA
Cenedeze
Simone Aparecida
SA
Teixeira
Marcelo Nicolas
MN
Muscara
Katia Regina
KR
Perez
Iolanda Midea
IM
Cuccovia
Alvaro
A
Pacheco-Silva
Giselle Martins
GM
Gonçalves
Niels Olsen Saraiva
NO
Camara
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005355:Fibrosis; D006410:Hematopoiesis; D007109:Immunity / Q000276:immunology*; D018664:Interleukin-12 / Q000378:metabolism; D015847:Interleukin-4 / Q000172:deficiency; D007668:Kidney / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology; D007674:Kidney Diseases / Q000276:immunology / Q000473:pathology / Q000503:physiopathology; D007677:Kidney Function Tests; D008026:Ligation; D008262:Macrophage Activation / Q000276:immunology*; D008264:Macrophages / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism*; D015398:Signal Transduction / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D014513:Ureter / Q000473:pathology; D014517:Ureteral Obstruction / Q000150:complications / Q000276:immunology / Q000473:pathology
D016207:Cytokines; D053594:Myeloid Differentiation Factor 88; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D018664:Interleukin-12; D015847:Interleukin-4