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Abstract Number: 1770

Assessing S100A4 and Myofibroblast Phenotypes in the Pathogenesis of Cardiac and Cutaneous Neonatal Lupus

Nalani Sachan1, Christina Firl2, Philip Carlucci3, Nicola Fraser2, Robert Clancy4 and Jill Buyon5, 1NYU Grossman School of Medicine, New York, NY, 2NYU Langone Health, New York, NY, 3New York University School of Medicine, New York, NY, 4Columbia University Medical Center, New York, NY, 5New York University Grossman School of Medicine, New York, NY

Meeting: ACR Convergence 2024

Keywords: Fibroblasts, Dermal, Fibroblasts, Other, interferon, pregnancy, Systemic lupus erythematosus (SLE)

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Session Information

Date: Monday, November 18, 2024

Title: Pediatric Rheumatology – Basic Science Poster

Session Type: Poster Session C

Session Time: 10:30AM-12:30PM

Background/Purpose: Neonatal lupus (NL), driven by fetal exposure to maternal anti-SSA/Ro autoantibodies, typically results in permanent cardiac manifestations in utero and/or a transient rash postnatally. Considering the contribution of fibrosis to the pathogenesis of organ injury and implications with regard to therapeutic approach in NL, this study was initiated to investigate molecular underpins of fetal cardiac and neonatal dermal fibroblasts in the context of maternal anti-Ro-propagated injury.

Methods: In an in vitro model of anti-Ro-initiated scarring, 2nd trimester human fetal cardiac fibroblasts or neonatal dermal fibroblasts were co-cultured with supernatants (sup) from THP-1 macrophages transfected with hY3 (noncoding ssRNA and TLR 7/8 agonist binding Ro60), TGF-β or IFNα for 24-72 hrs. Relative fibroblast heterogeneity was confirmed through the expression of S100 Calcium-Binding Protein A4 (S100A4) and/or myofibroblast marker α-SMA. Functional fibroblast readouts—cell migration and wound closure—were assessed by scratch assay.  

Results: Immunofluorescence evaluated 24, 48, and 72 hrs after treatment (DOTAP sup, hY3 sup or IFNα or TGF-β1) established a time-course of S100A4 and α-SMA expression in cardiac fibroblasts (Fig 1A) and dermal fibroblasts (Fig 2A). At 24 hrs following the addition of hY3 sup or IFNα, S100A4 expression predominated in both cell types.  By 48 hrs, cardiac and dermal fibroblasts showed increased α-SMA expression, primarily through the emergence of a dual-positive (α-SMA+ S100A4+) subpopulation (Fig 1A). At 72 hrs, three subpopulations (S100A4+, α-SMA+, and dual α-SMA+S100A4+) were observed in fetal cardiac fibroblasts treated with hY3 sup or IFNα, with the α-SMA+ population being most prominent (Fig 1A). In contrast, the proportion of α-SMA+ myofibroblasts was markedly diminished in the dermal fibroblasts at 72 hrs (Fig 2).  Neutralizing antibodies to IFNα inhibited α-SMA and S100A4 expression in cardiac and dermal fibroblasts cultured with hY3 sup, validating type I IFN as a dominant cytokine (Fig 1B and Fig 2B). Inhibition of S100A4 by niclosamide markedly attenuated S100A4 expression after IFNα treatment of the cardiac fibroblasts (Fig 1C). Turning to fibroblast function, hY3 sup and/or IFNα resulted in rapid wound closure after 24 hrs as indicated by a smaller gap area in the cardiac fibroblasts (Fig 3A and C) and in dermal fibroblasts (Fig 3B and D). Niclosamide mitigated the wound area closure after 24 hrs in both cardiac and dermal fibroblasts cultured with hY3 sup or IFNα (Fig 3).

Conclusion: These results suggest that in NL, the initial macrophage-fibroblast injury mediated by anti-Ro is driven by macrophage secreted type I IFN. Resultant S100A4 expression triggers cardiac fibroblasts to transdifferentiate into myofibroblasts which is not sustained in dermal fibroblasts, consistent with the transient clinical phenotype of cutaneous NL. Pathologic cardiac and dermal fibroblast migration appears dependent largely on S100A4 rather than α-SMA. Niclosamide treatment effectively inhibits fibroblast migratory and profibrotic functions, suggesting a role in the therapeutic approach to NL which may be applicable to other organ injury.   

Supporting image 1

Figure 1. (A) Human fetal cardiac fibroblasts treated with DOTAP mac sup (1:5 dilution), hY3 mac sup (1:5), IFNα (2000U/mL), or activated TGF-β1 (2 ng/mL) for 24-72 hours (N=3). (B) Human fetal cardiac fibroblasts treated with DOTAP mac sup, hY3 mac sup, IFNα, or TGF-β1 separately (upper panel) or in combination with NAb to IFNα added at t=0 (lower panel) (N=3). (C) Fetal cardiac fibroblasts treated with niclosamide (N), S100A4 inhibitor along with IFNα or TGF-β1 (N=2).

Supporting image 2

Figure 2. (A) Human neonatal dermal fibroblasts treated with DOTAP mac sup (1:5 dilution), hY3 mac sup (1:5), IFNα (2000U/mL), or TGF-β1 (2 ng/mL) for 24-72 hours (N=2). (B) Human neonatal dermal fibroblasts treated with DOTAP mac sup, hY3 mac sup, IFNα, or TGF-β1 separately (upper panel) or in combination with NAb to IFNα added at t=0 (lower panel) (N=3).

Supporting image 3

Figure 3. (A) Human fetal cardiac fibroblasts and (B) human neonatal dermal fibroblasts were treated with DOTAP mac sup (1:5 dilution), hY3 mac sup (1:5), TGF-β1 (2 ng/mL), IFNα (2000 U/mL) separately and in combination with niclosamide (150 nM) for 24 hours. (C and D) Scratch was made at t=0 and wound closure (% area) was assessed at t=24 hours.


Disclosures: N. Sachan: None; C. Firl: None; P. Carlucci: None; N. Fraser: None; R. Clancy: None; J. Buyon: Artiva Biotherapeutics, 1, Bristol-Myers Squibb(BMS), 1, 2, Equillium, 1, GlaxoSmithKlein(GSK), 1, 2, Otsuka Pharmaceuticals, 1, Related Sciences, 1, 2.

To cite this abstract in AMA style:

Sachan N, Firl C, Carlucci P, Fraser N, Clancy R, Buyon J. Assessing S100A4 and Myofibroblast Phenotypes in the Pathogenesis of Cardiac and Cutaneous Neonatal Lupus [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/assessing-s100a4-and-myofibroblast-phenotypes-in-the-pathogenesis-of-cardiac-and-cutaneous-neonatal-lupus/. Accessed .
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All abstracts accepted to ACR Convergence are under media embargo once the ACR has notified presenters of their abstract’s acceptance. They may be presented at other meetings or published as manuscripts after this time but should not be discussed in non-scholarly venues or outlets. The following embargo policies are strictly enforced by the ACR.

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