title: TLR-mediated albuminuria needs TNFα-mediated cooperativity between TLRs present in hematopoietic tissues and CD80 present on non-hematopoietic tissues in mice.
abstract: Transient albuminuria induced by pathogen-associated molecular patterns (PAMPs) in mice through engagement of Toll-like receptors (TLRs) is widely studied as a partial model for some forms of human nephrotic syndrome (NS). In addition to TLRs, CD80 has been shown to be essential for PAMP-mediated albuminuria. However, the mechanistic relationships between TLRs, CD80 and albuminuria remain unclear. Here, we show that albuminuria and CD80-uria induced in mice by many TLR ligands are dependent on the expression of TLRs and their downstream signalling intermediate MyD88 exclusively in hematopoietic cells and, conversely, on CD80 expression exclusively in non-hematopoietic cells. TNFα is crucial for TLR-mediated albuminuria and CD80-uria, and induces CD80 expression in cultured renal podocytes. IL-10 from hematopoietic cells ameliorates TNFα production, albuminuria and CD80-uria but does not prevent TNFα-mediated induction of podocyte CD80 expression. Chitohexaose, a small molecule originally of parasite origin, mediates TLR4-dependent anti-inflammatory responses, and blocks TLR-mediated albuminuria and CD80-uria through IL-10. Thus, TNFα is a prominent mediator of renal CD80 induction and resultant albuminuria in this model, and small molecules modulating TLR-mediated inflammatory activation might have contributory or adjunct therapeutic potential in some contexts of NS development.
authors.affiliation: National Institute of Immunology, New Delhi 110067, India.
authors.forename: Nidhi
authors.initials: N
authors.lastname: Jain
authors.affiliation: Pediatric Biology Center, Translational Health Sciences and Technology Institute, Faridabad 121001, National Capital Region, India.
authors.forename: Bhavya
authors.initials: B
authors.lastname: Khullar
authors.affiliation: National Institute of Immunology, New Delhi 110067, India.
authors.forename: Neelam
authors.initials: N
authors.lastname: Oswal
authors.affiliation: National Institute of Immunology, New Delhi 110067, India.
authors.forename: Balaji
authors.initials: B
authors.lastname: Banoth
authors.affiliation: Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Prashant
authors.initials: P
authors.lastname: Joshi
authors.affiliation: Institute of Life Sciences, Bhubaneswar, India.
authors.forename: Balachandran
authors.initials: B
authors.lastname: Ravindran
authors.affiliation: Department of Pathology, All India Institute of Medical Sciences, New Delhi, India.
authors.forename: Subrat
authors.initials: S
authors.lastname: Panda
authors.affiliation: National Institute of Immunology, New Delhi 110067, India.
authors.forename: Soumen
authors.initials: S
authors.lastname: Basak
authors.affiliation: National Institute of Immunology, New Delhi 110067, India.
authors.forename: Anna
authors.initials: A
authors.lastname: George
authors.affiliation: National Institute of Immunology, New Delhi 110067, India Pediatric Biology Center, Translational Health Sciences and Technology Institute, Faridabad 121001, National Capital Region, India.
authors.forename: Satyajit
authors.initials: S
authors.lastname: Rath
authors.affiliation: National Institute of Immunology, New Delhi 110067, India Pediatric Biology Center, Translational Health Sciences and Technology Institute, Faridabad 121001, National Capital Region, India vineeta@nii.res.in.
authors.forename: Vineeta
authors.identifier: 0000-0002-8995-2045
authors.initials: V
authors.lastname: Bal
authors.affiliation: Pediatric Biology Center, Translational Health Sciences and Technology Institute, Faridabad 121001, National Capital Region, India.
authors.forename: Shailaja
authors.initials: S
authors.lastname: Sopory
mesh_terms: D000419:Albuminuria / Q000378:metabolism*; D000818:Animals; D018122:B7-1 Antigen / Q000378:metabolism*; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D006410:Hematopoiesis / Q000187:drug effects; D016753:Interleukin-10 / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009844:Oligosaccharides / Q000494:pharmacology; D050199:Podocytes / Q000187:drug effects / Q000378:metabolism; D011070:Poly I-C / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D051193:Toll-Like Receptors / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D018122:B7-1 Antigen; D009844:Oligosaccharides; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; C050523:chitohexaose; D011070:Poly I-C
keywords: CD80; IL-10; Proteinuria; TLR; TNFα