TY - JOUR
T1 - Reprogramming of profibrotic macrophages for treatment of bleomycin-induced pulmonary fibrosis
AU - Zhang, Fenghua
AU - Ayaub, Ehab A.
AU - Wang, Bingbing
AU - Puchulu-Campanella, Estela
AU - Li, Yen Hsing
AU - Hettiarachchi, Suraj U.
AU - Lindeman, Spencer D.
AU - Luo, Qian
AU - Rout, Sasmita
AU - Srinivasarao, Madduri
AU - Cox, Abigail
AU - Tsoyi, Konstantin
AU - Nickerson-Nutter, Cheryl
AU - Rosas, Ivan O.
AU - Low, Philip S.
N1 - Funding Information:
This study was supported by a gift from Three Lakes Partners, LLC. We thank Victor Bernal-Crespo and the Purdue University Histology Research Laboratory for staining lung samples.
Publisher Copyright:
© 2020 The Authors. Published under the terms of the CC BY 4.0 license
PY - 2020/8/7
Y1 - 2020/8/7
N2 - Fibrotic diseases cause organ failure that lead to ~45% of all deaths in the United States. Activated macrophages stimulate fibrosis by secreting cytokines that induce fibroblasts to synthesize collagen and extracellular matrix proteins. Although suppression of macrophage-derived cytokine production can halt progression of fibrosis, therapeutic agents that prevent release of these cytokines (e.g., TLR7 agonists) have proven too toxic to administer systemically. Based on the expression of folate receptor β solely on activated myeloid cells, we have created a folate-targeted TLR7 agonist (FA-TLR7-54) that selectively accumulates in profibrotic macrophages and suppresses fibrosis-inducing cytokine production. We demonstrate that FA-TLR7-54 reprograms M2-like fibrosis-inducing macrophages into fibrosis-suppressing macrophages, resulting in dramatic declines in profibrotic cytokine release, hydroxyproline biosynthesis, and collagen deposition, with concomitant increases in alveolar airspaces. Although nontargeted TLR7-54 is lethal at fibrosis-suppressing doses, FA-TLR7-54 halts fibrosis without evidence of toxicity. Taken together, FA-TLR7-54 is shown to constitute a novel and potent approach for treating fibrosis without causing dose-limiting systemic toxicities.
AB - Fibrotic diseases cause organ failure that lead to ~45% of all deaths in the United States. Activated macrophages stimulate fibrosis by secreting cytokines that induce fibroblasts to synthesize collagen and extracellular matrix proteins. Although suppression of macrophage-derived cytokine production can halt progression of fibrosis, therapeutic agents that prevent release of these cytokines (e.g., TLR7 agonists) have proven too toxic to administer systemically. Based on the expression of folate receptor β solely on activated myeloid cells, we have created a folate-targeted TLR7 agonist (FA-TLR7-54) that selectively accumulates in profibrotic macrophages and suppresses fibrosis-inducing cytokine production. We demonstrate that FA-TLR7-54 reprograms M2-like fibrosis-inducing macrophages into fibrosis-suppressing macrophages, resulting in dramatic declines in profibrotic cytokine release, hydroxyproline biosynthesis, and collagen deposition, with concomitant increases in alveolar airspaces. Although nontargeted TLR7-54 is lethal at fibrosis-suppressing doses, FA-TLR7-54 halts fibrosis without evidence of toxicity. Taken together, FA-TLR7-54 is shown to constitute a novel and potent approach for treating fibrosis without causing dose-limiting systemic toxicities.
KW - bleomycin
KW - folate receptor β
KW - idiopathic pulmonary fibrosis
KW - macrophages
KW - toll-like receptor 7
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U2 - 10.15252/emmm.202012034
DO - 10.15252/emmm.202012034
M3 - Article
C2 - 32597014
AN - SCOPUS:85087291646
SN - 1757-4676
VL - 12
SP - e12034
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
IS - 8
M1 - e12034
ER -