Inhibiting triggering receptor expressed on myeloid cells 1 signaling to ameliorate skin fibrosis
Swarna Bale, Priyanka Verma, Bharath Yalavarthi, Matija Bajželj, Syed A.M. Hasan, Jenna N. Silverman, Katherine Broderick, Kris A. Shah, Timothy Hamill, Dinesh Khanna, Alexander B. Sigalov, Swati Bhattacharyya, John Varga
Swarna Bale, Priyanka Verma, Bharath Yalavarthi, Matija Bajželj, Syed A.M. Hasan, Jenna N. Silverman, Katherine Broderick, Kris A. Shah, Timothy Hamill, Dinesh Khanna, Alexander B. Sigalov, Swati Bhattacharyya, John Varga
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Research Article Infectious disease

Inhibiting triggering receptor expressed on myeloid cells 1 signaling to ameliorate skin fibrosis

Abstract

Systemic sclerosis (SSc) is characterized by immune system failure, vascular insult, autoimmunity, and tissue fibrosis. TGF-β is a crucial mediator of persistent myofibroblast activation and aberrant extracellular matrix production in SSc. The factors responsible for this are unknown. By amplifying pattern recognition receptor signaling, triggering receptor expressed on myeloid cells 1 (TREM-1) is implicated in multiple inflammatory conditions. In this study, we used potentially novel ligand-independent TREM-1 inhibitors in preclinical models of fibrosis and explanted SSc skin fibroblasts in order to investigate the pathogenic role of TREM-1 in SSc. Selective pharmacological TREM-1 blockade prevented and reversed skin fibrosis induced by bleomycin in mice and mitigated constitutive collagen synthesis and myofibroblast features in SSc fibroblasts in vitro. Our results implicate aberrantly activated TREM-1 signaling in SSc pathogenesis, identify a unique approach to TREM-1 blockade, and suggest a potential therapeutic benefit for TREM-1 inhibition.

Authors

Swarna Bale, Priyanka Verma, Bharath Yalavarthi, Matija Bajželj, Syed A.M. Hasan, Jenna N. Silverman, Katherine Broderick, Kris A. Shah, Timothy Hamill, Dinesh Khanna, Alexander B. Sigalov, Swati Bhattacharyya, John Varga

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Figure 4

TREM-1 signaling is activated in SSc skin.

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TREM-1 signaling is activated in SSc skin. (A) Skin biopsies from patien...
(A) Skin biopsies from patients with SSc (n = 8) and individuals acting as healthy controls (n = 4) were immunolabeled with antibodies against pSyk or ASMA, and immunofluorescence was visualized by Nikon A1R laser scanning confocal microscope. The percentage of immuno-positive cells (mean percentages from 4 randomly selected regions) was quantified. Mann-Whitney U test. P values are shown. Original magnification, ×40. (B) Confluent SSc skin fibroblasts (n = 8, top; n = 3, bottom) were incubated with GF9 for 24 hours, and mRNA levels were quantitated by real-time quantitative PCR. Results were normalized with GAPDH and are shown as the mean ± SD of triplicate determinations from individual patients. Paired t test. P values are shown. (C) SSc fibroblasts (n = 6) were immunolabeled using antibodies against collagen I, ASMA, or pSyk. Scale bar: 100 μm. Representative images and relative fluorescence intensities (mean ± SEM from 3 randomly selected regions) are shown.