Lupus: Open Access
Open Access

Precision Targeting of NF-kB Signaling in Lupus Nephritis

Dawn J. Caster and David W. Powell^{* *}Correspondence: David W. Powell, Department of Biochemistry and Molecular Genetics, Division of Nephrology and Hypertension, University of Louisville, Kentucky, USA, Tel: +1- 502-475-3610, Email:

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About the Study

NF-κB controls the expression of the cytokines/chemokines and other immune modulators that mediate the cellular and molecular events in the LN pathogenesis [1,2]. These events include loss of immune tolerance from impaired myeloid cell apoptosis and clearance and release of nuclear products, activation of auto-reactive T cells and subsequent B cell activation and production of autoantibodies and formation of circulating Immune Complexes (IC), and glomerular infiltration and activation of inflammatory cells (neutrophils, monocytes) following IC deposition [3-6]. Many of the environmental triggers for LN activate these cellular processes and NF-κB through toll-like receptors (TLR) [7].

Variants in several genes that express components in the TLR/NF-κB signaling axis were identified in association with LN, including TLR 3/7/9, MYD88, IRAK1, TNFAIP3, and TNIP1 [3]. Brady et al. recently reviewed the associate of TNIP1 polymorphisms with LN [8]. Of the five primary TNIP1 polymorphisms identified as risks for SLE, only two (rs7708392 and rs4958881) have been confirmed with association with LN. TNIP1 expresses ABIN1, a polyubiquitin binding protein that functions as a physiological inhibitor of NF-κB by binding to polyubiquitin moieties on upstream regulators and this process is also facilitated by ABIN1 coupling with A20, the product of TNFAIP3 [9]. Nanda et al. reported that transgenic mice expressing an ABIN1 mutation (ABIN1[D485N]) disrupting the NF-κB inhibitory function spontaneously and progressively develop a number of SLE-associated phenotypes, including splenomegaly and elevated circulating IC and pathogenic antinuclear antibody (ANA) and Anti-ds DNA autoantibodies [5]. This report also showed that TLR 1-9-stimulated NF-κB activation was enhanced in myeloid and B cells isolated from ABIN1[D485N] mice, as compared with cells from wild-type mice. Caster et al. reported that ABIN1 [D485N] mice also develop progressive glomerulonephritis (GN) with pathologic features of the most common and severe form of human LN (Class IV) [4]. Nanda et al. have also reported that MYD88 and TLR7 deficiency and inhibition of IRAK1 and IRAK4 kinase activity suppressed the development of autoimmunity and LN in ABIN1[D485N] mice [5,10,11]. Kuriakose et al. showed that ABIN1 deficient mice also spontaneously develop SLEassociated autoimmune phenotypes and progressive, proliferative immune complex-mediated GN and that MYD88 and TLR7/9 deficiency suppressed development of GN in these mice [6].

Collectively, these findings suggest that TNIP1 variants and resulting loss of ABIN1 molecular function contribute to development of SLE and LN due to uncontrolled regulation and subsequent enhanced NF-κB activation through the TLR7/9/ MYD88/IRAK1/4 signaling axis. This suggests that pharmacologic inhibition of TLRs, MYD88, and IRAK1/4 could provide viable precision treatment options for LN in patients with rs7708392 and rs4958881 variants in TNIP1 or variants in other NF-κB regulatory genes. Another promising therapeutic direction for patients with these genotypes is use of monoclonal antibodies against NF-κB effector molecules that are implicated in LN, such as IFNs, IL-6, IL-17, IL-23, and IP-10. Several monoclonal antibodies targeting these cytokines are in development or approved for other indications. Anifrolumab, a human monoclonal antibody to type I interferon reduced SLE activity in patients with moderately to severe SLE and is currently being evaluated in LN (NCT02547922) [12]. IL-6 receptor inhibitors have been FDA approved for rheumatoid arthritis (sarilumab, tocilizumab). Sirukumab, an anti- IL-6 monoclonal antibody failed to show efficacy in LN, but the investigators comment that a small subset of subjects appeared to have response to therapy [13]. Multiple IL-17 and IL-23 inhibitors are used for the treatment of psoriasis (IL-17: ixekizumab, brodalumab, secukinumab; IL-23: guselkumab, risankizumab), but have not been evaluated in SLE and LN.

Conclusion

The identification of SLE and LN patients who have enhanced NF-κB activation and have elevated levels of effector cytokines may predict which patients are most likely to benefit from these specific treatments.

References

1. Almaani S, Meara A, Rovin HB. Update on lupus nephritis. Clin J Am Soc Nephrol. 2017;12(5):825-835.
2. Zubair A, Frieri M. NF-kappa B and systemic lupus erythematosus: examining the link. J Nephrol. 2013;26(6):953-959.
3. Munroe ME, James AJ. Genetics of lupus nephritis: clinical implications. Semin Nephrol. 2015;35(5):396-409.
4. Caster DJ, Korte EA, Nanda SK, Oliver RK, G'sell RT, Sheehan RM, et al. ABIN1 dysfunction as a genetic basis for lupus nephritis. J Am Soc Nephrol. 2013;24(11):1743-1754.
5. Nanda SK, Venigalla RK, Ordureau A, Patterson-Kane JC, Powell DW, Toth R,  et al. Polyubiquitin binding to ABIN1 is required to prevent autoimmunity. J Exp Med. 2011;208(6):1215-1228.
6. Kuriakose J, Redecke V, Guy C, Zhou J, Wu R, Ippagunta SK, et al. Patrolling monocytes promote the pathogenesis of early lupus-like glomerulonephritis. J Clin Invest. 2019;129(6):2251-2265.
7. Mitchell SJ, Vargas, Hoffmann A. Signaling via the NF kappa B system. Wiley Interdisciplinary Reviews-Systems Biology and Medicine. 2016;8(3):227-241.
8. Brady MP, Korte AK, Caster JD, Powell WD. TNIP1/ABIN1 and lupus nephritis: Review. Lupus Sci Med. 2020;7(1):1-5.
9. G'Sell RT, Gaffney PM, Powell DW. ABIN1 a physiological inhibitor of NF-kappaB: A molecular switch for inflammation and autoimmunity. Arthritis Rheumatol. 2015;67(9):2-6.
10. Nanda SK, Lopez-Pelaez M, Arthur JS, Marchesi F, Cohen P. Suppression of IRAK1 or IRAK4 Catalytic Activity, but Not Type 1 IFN Signaling, Prevents Lupus Nephritis in Mice Expressing a Ubiquitin Binding-Defective Mutant of ABIN1. J Immunol, 2016;197(11):4266-4273.
11. Nanda SK, Petrova T, Marchesi F, Gierlinski M, Razsolkov M, Lee KL, et al. Distinct signals and immune cells drive liver pathology and glomerulonephritis in ABIN1[D485N] mice. Life Sci Alliance. 2019; 2(6): e201900533.
12. Morand EF, Furie R, Tanaka Y, Bruce IN, Richez C, Bae SC, et al. Trial of Anifrolumab in Active Systemic Lupus Erythematosus. N Engl J Med. 2020;382(5):211-221.
13. Rovin HB, van Vollenhoven RF, Aranow C, Wagner C, Gordon R, Zhuang Y, et al. A Multicenter, Randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of treatment with Sirukumab (CNTO 136) in patients with active lupus nephritis. Arthritis Rheumatol. 2016;68(9):2174-83.