An Autotaxin/Lysophosphatidic Acid/Interleukin‐6 Amplification Loop Drives Scleroderma Fibrosis

Abstract

Objective We previously implicated the lipid mediator lysophosphatidic acid (LPA) in dermal fibrosis in systemic sclerosis (SSc). Here we identify the role of the LPA-producing enzyme autotaxin (ATX), and connect the ATX-LPA and IL-6 pathways in SSc. Methods We evaluated a novel ATX inhibitor, PAT-048, on fibrosis and IL-6 expression in the bleomycin (BLM) mouse model of dermal fibrosis. We utilized SSc patient and control dermal fibroblasts to evaluate LPA induction of IL-6, and IL-6 induction of ATX. We next evaluated whether LPA-induced ATX expression is dependent on IL-6, and whether baseline IL-6 expression in SSc fibroblasts is dependent on ATX. Finally, we compared ATX and IL-6 expression in SSc and healthy subject skin. Results PAT-048 markedly attenuated BLM-induced dermal fibrosis when initiated before or after fibrosis development. LPA stimulated human dermal fibroblast IL-6 expression, and IL-6 stimulated fibroblast ATX expression, connecting the ATX-LPA and IL-6 pathways in an amplification loop. IL-6 knockdown abrogated LPA-induced ATX expression in fibroblasts, and ATX inhibition attenuated IL-6 expression in fibroblasts and the skin of BLM-challenged mice. Both ATX and IL-6 expression were increased in SSc skin, and LPA-induced IL-6 levels and IL-6-induced ATX levels were increased in SSc fibroblasts compared to controls. Conclusion ATX is required for the development and maintenance of dermal fibrosis in the BLM model and enables two major mediators of SSc fibrogenesis, LPA and IL-6, to amplify each other’s production. Our results suggest that concurrent inhibition of these two pathways may be an effective therapeutic strategy for SSc fibrosis.

Lysophosphatidic Acid Receptor 1 Antagonist SAR100842 for Patients With Diffuse Cutaneous Systemic Sclerosis

“…A common toxicologic concern with antifibrotic agents is whether patients may exhibit a delay in normal wound healing. Studies with LPA receptor antagonists using incisional and excisional wounding in rats have been reassuring , but it is noteworthy that in the present study, although one‐third of patients had digital ulcerations at baseline, no overt safety concerns emerged for them, confirming the good safety profile in SSc patients.…”

“…Of greatest interest, it appears that it may contribute to excessive tissue fibrosis, mainly through LPA 1 receptor activation , as observed in SSc. Recent findings further emphasize the key roles of autotaxin and the LPA axis in SSc . SAR100842 is a low molecular weight, selective inhibitor of the LPA 1 receptor that is being developed as a potential novel therapy for SSc with the aim of reducing or even reversing the progression of fibrosis.…”

Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae

“…If inflammation is not resolved, chronic activation of ATX-LPA-inflammatory signaling and the wound healing response becomes maladaptive [30,32] in diseases such as pulmonary fibrosis, cirrhosis, rheumatoid arthritis, inflammatory bowel disease, and cancers [24,48]. Many inflammatory conditions are accompanied by fibrosis, a process driven through LPAR1 signaling and further mediated through inflammatory cytokines [49][50][51][52][53][54][55][56][57][58][59][60][61]. This is why an ATX inhibitor, GLPG1690 [62] and an LPAR1 antagonist (BMS986020) [63] attenuated idiopathic pulmonary fibrosis in Phase IIa clinical trials.…”

Implications for breast cancer treatment from increased autotaxin production in adipose tissue after radiotherapy

“…This could protect residual breast cancer cells against further fractions of radiotherapy, thereby limiting the efficacy of the overall treatment. In addition, increased signaling by LPA, especially via LPA 1 receptors, is associated with the development of fibrosis in various organs (41)(42)(43)(44)(45); therefore, if irradiating breast adipose tissue increased LPA signaling, together with an inflammatory response, this could contribute to radiation-induced fibrosis.…”