Toll-like receptor 9 (TLR9) is a regulator of disease pathogenesis in systemic lupus erythematosus (SLE). Why TLR9 represses disease while TLR7 and MyD88 have the opposite effect remains undefined. To begin to address this question, we created 2 alleles to manipulate TLR9 expression, allowing for either selective deletion or overexpression. We used these to test cell type–specific effects of Tlr9 expression on the regulation of SLE pathogenesis. Notably, Tlr9 deficiency in B cells was sufficient to exacerbate nephritis while extinguishing anti–nucleosome antibodies, whereas Tlr9 deficiency in dendritic cells (DCs), plasmacytoid DCs, and neutrophils had no discernable effect on disease. Thus, B cell–specific Tlr9 deficiency unlinked disease from autoantibody production. Critically, B cell–specific Tlr9 overexpression resulted in ameliorated nephritis, opposite of the effect of deleting Tlr9. Our findings highlight the nonredundant role of B cell–expressed TLR9 in regulating lupus and suggest therapeutic potential in modulating and perhaps even enhancing TLR9 signals in B cells.
Jeremy S. Tilstra, Shinu John, Rachael A. Gordon, Claire Leibler, Michael Kashgarian, Sheldon Bastacky, Kevin M. Nickerson, Mark J. Shlomchik
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JCI Insight | 2023 |
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Tilstra JS, Kim M, Gordon RA, Leibler C, Cosgrove HA, Bastacky S, Nickerson KM, Shlomchik MJ |
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For whom the B(c)ell tolls: CXCL4 AIDs human autoimmunity
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The Role of the Oxidative State and Innate Immunity Mediated by TLR7 and TLR9 in Lupus Nephritis
Echavarria R, Cardona-Muñoz EG, Ortiz-Lazareno P, Andrade-Sierra J, Gómez-Hermosillo LF, Casillas-Moreno J, Campos-Bayardo TI, Román-Rojas D, García-Sánchez A, Miranda-Díaz AG |
International journal of molecular sciences | 2023 |
TLR9 ligand sequestration by chemokine CXCL4 negatively affects central B cell tolerance.
Çakan E, Ah Kioon MD, Garcia-Carmona Y, Glauzy S, Oliver D, Yamakawa N, Vega Loza A, Du Y, Schickel JN, Boeckers JM, Yang C, Baldo A, Ivashkiv LB, Young RM, Staudt LM, Moody KL, Nündel K, Marshak-Rothstein A, van der Made CI, Hoischen A, Hayward A, Rossato M, Radstake TRDJ, Cunningham-Rundles C, Ryu C, Herzog EL, Barrat FJ, Meffre E |
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Wang Z, Hu D, Pei G, Zeng R, Yao Y |
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Heightened TLR7 signaling primes BCR-activated B cells in chronic graft-versus-host disease for effector functions
Bracken SJ, Suthers AN, DiCioccio RA, Su H, Anand S, Poe JC, Jia W, Visentin J, Basher F, Jordan CZ, McManigle WC, Li Z, Hakim FT, Pavletic SZ, Bhuiya NS, Ho VT, Horwitz ME, Chao NJ, Sarantopoulos S |
Blood Advances | 2023 |
Triad3A-Mediated K48-Linked ubiquitination and degradation of TLR9 impairs mitochondrial bioenergetics and exacerbates diabetic cardiomyopathy
Kong C, Guo Z, Liu F, Tang N, Wang M, Yang D, Li C, Yang Z, Ma Y, Wang P, Tang Q |
Journal of Advanced Research | 2023 |