Studies on the regulatory roles for Retinoic Acid (RA) during host-microbial interaction : implications for S. aureus and C. albicans infections

Abstract

Chronic inflammatory disorder is one of the leading causes of death worldwide. Association between pathogenic infection and inflammation governs tissue homeostasis, which relies on extensive crosstalk among signaling networks. Interestingly, vitamin A deficiency is known to effectuate several aberrations in innate and adaptive immune responses and play a central role in governing fate of diseases. In this regard, our current study involves exploration of regulatory role of vitamin A metabolite – Retinoic Acid (RA) in modulating host-microbial interaction to mitigate inflammatory disorders. In this context, thesis delineates regulatory effects of RA during C. albicans induced delayed wound healing and pathogenesis. In this regard, our observation with RA treatment showed significant rescue of C. albicans induced wound healing delay. Data was corroborated with skewed anti-inflammatory response, as proinflammatory genes (Cxcl1, Tnf and IL-6) were suppressed and excessive activation of anti-inflammatory M2 macrophages genes (Retnl, Cxc3r1 and Ucp1) was observed. BMP signaling which was established previously for its significant contribution to wound delay, was abrogated upon treatment with RA. Mechanistically, RA treatment showed enhanced phagocytic uptake of C. albicans through targeted inhibition of an actin-binding protein, cofilin. It governs such effect through inhibition of C.albicans induced BMP signaling which was further found to crosstalk with down-stream effectors of Rho/Rac GTPases. Thus, current work explores the beneficial effects of RA in orchestrating tissue homeostasis. Septic arthritis is a joint inflammatory disorder caused by bacterial invasion to cartilages which eventually disseminate to the bones. The disease progression is driven by macrophage infiltration into the associated synovial joints. However, the factors mediating such inflammatory dysfunction remain obscure. In our current study, we have uncovered a critical role for Aurora kinase A driven activation of mTOR-WNT signalling axis, which acts as a key regulator of pro-inflammatory cytokine expression in joint synovium. With the limited treatment modalities, utilization of vitamins therapy was explored as a potential interface for the development of efficacious adjuncts against pathogen-driven responses. Interestingly, we found that prophylactic treatment of RA, rescued inflammatory damage and helped in preservation of articular cartilage and bone architecture. Mechanistically, adapalene treatment inhibited WNT signalling with a concomitant activation of HIPPO signalling, generating alternatively activated macrophages. Along these lines, silencing of MST1/2 attenuated the ability of adapalene to induce pro-resolving mediators. This resulted in significant decrease of synovial inflammation and septic arthritis development. Thus, the current work uncovered the potential therapeutic effects of vitamin A metabolite contributing to suppression of hyper-inflammation and tissue repair. A possible correlation between activity of RA and disease burden in host was observed. On one side potential contribution of Hippo signalling was found to govern anti-inflammatory effects of RA, which suppressed S.aureus induced septic arthritis. On the other hand, a significant inhibition of BMP signalling as attributed to RA treatment resulted in enhanced wound healing during C.albicans infection.