779 Deficiency of the TLR4 inhibitory homolog RP105 exacerbates fibrosis
نویسندگان
چکیده
The pathogenic networks of immune, vascular, and fibrotic processes underlying non-resolving fibrosis in SSc remain poorly understood. Our previous studies demonstrated that while TLR4 its cognate damage-associated endogenous ligands (DAMPs) elicited potent profibrotic effects myofibroblasts activation, genetic targeting or DAMPs mice accelerated resolution. To prevent aberrant DAMP-TLR4 signaling, a variety negative regulators evolved to dampen the magnitude duration signaling. Radioprotective 105 KDa (RP105), homolog, competitively inhibits DAMP recognition ,and block signaling immune cells. However, role RP105 TLR4-depedent responses is unknown. Using unbiased transcriptome analysis skin biopsies, we found both adaptor MD2 were elevated significantly correlated with each other (r=-0.54, p=0.0062). In contrast, levels MD1 failed show significant elevation association (r=-0.35, p=0.11). Notably, expression was negatively associated marker alpha-smooth muscle actin (ASMA) fibroblasts (r=-0.53). vitro, exogenous abrogated DAMP-induced responses, RP105-depleted showed exaggerated responses. Importantly, vivo ablation aggravated complementary disease models augmented Thus, identify RP105-MD1 as novel cell-intrinsic regulator TLR4-MD1-driven sustained fibroblast constituting critical regulatory network governing process. Moreover, propose impaired function might contribute progression disease.
منابع مشابه
Deficiency of the TLR4 analogue RP105 aggravates vein graft disease by inducing a pro-inflammatory response
Venous grafts are often used to bypass occlusive atherosclerotic lesions; however, poor patency leads to vein graft disease. Deficiency of TLR4, an inflammatory regulator, reduces vein graft disease. Here, we investigate the effects of the accessory molecule and TLR4 analogue RadioProtective 105 (RP105) on vein graft disease. RP105 deficiency resulted in a 90% increase in vein graft lesion area...
متن کاملDeficiency of tumour necrosis factor-related apoptosis-inducing ligand exacerbates lung injury and fibrosis
BACKGROUND The death receptor ligand tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) shows considerable clinical promise as a therapeutic agent. TRAIL induces leukocyte apoptosis, reducing acute inflammatory responses in the lung. It is not known whether TRAIL modifies chronic lung injury or whether TRAIL has a role in human idiopathic pulmonary fibrosis (IPF). We therefore exp...
متن کاملCutting edge: regulation of TLR4-driven B cell proliferation by RP105 is not B cell autonomous.
Mechanistic understanding of RP105 has been confounded by the fact that this TLR homolog has appeared to have opposing, cell type-specific effects on TLR4 signaling. Although RP105 inhibits TLR4-driven signaling in cell lines and myeloid cells, impaired LPS-driven proliferation by B cells from RP105(-/-) mice has suggested that RP105 facilitates TLR4 signaling in B cells. In this article, we sh...
متن کاملMicrosomal prostaglandin E synthase-1 deficiency exacerbates pulmonary fibrosis induced by bleomycin in mice.
Microsomal prostaglandin E2 synthase-1 (mPGES-1), an inducible enzyme that converts prostaglandin H2 (PGH2) to prostaglandin E2 (PGE2), plays an important role in a variety of diseases. So far, the role of mPGES-1 in idiopathic pulmonary fibrosis (IPF) remained unknown. The current study aimed to investigate the role of mPGES-1 in pulmonary fibrosis induced by bleomycin in mice. We found that m...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
ژورنال
عنوان ژورنال: Journal of Investigative Dermatology
سال: 2022
ISSN: ['1523-1747', '0022-202X']
DOI: https://doi.org/10.1016/j.jid.2022.05.792