Paudyal, Basudev (2018) Investigation of nanoparticles induced cell responses in the presence of innate immune factors. (PhD thesis), Kingston University, .
Abstract
Nanoparticles (NPs) are progressively being investigated for use in biomedical applications, including biological agents delivery like gene delivery, drug and protein delivery. Activation of complement pathways and interactions with immune recognition subcomponents can modulate the clearance of the NPs and subsequent inflammatory response. Such modulation could affect the intended translational applications either in the development as tissue-specific drug delivery platform or in the treatment of pulmonary diseases such as tuberculosis and lung cancer thus, poses challenges to develop them for in vivo applications. Here, we set out to study the interaction between innate immune components such as properdin, a small fragment of properdin, TSR4+5, a key lung pattern recognition molecule, surfactant protein D (SP-D), and carbon nanotubes (CNTs), and potential downstream effects on the immune response via macrophages. We report, that human properdin, an up-regulator of the complement alternative pathway and stabilizer of C3 convertase can opsonize CNTs via its thrombospondin type I repeat (TSR) 4 and 5. Uptake of properdin bound CNTs was enhanced by a macrophage cell line, THP-1, surging a robust pro-inflammatory immune response. In addition, recombinant TSR4+5 on CNTs, inhibited complement consumption, suggesting that TSR4+5, can be potentially used as a complement inhibitor in a number of pathological circumstances arising due to unintentional complement activation. Similarly, a recombinant fragment of human SP-D (rfhSP-D) bound to CNTs via its C-type lectin domain and augmented phagocytosis by THP-1 monocytic cell lines, together with an increased pro-inflammatory response. Furthermore, rfhSP-D opsozined CNTs continued to activate complement pathway via the classical pathway. Complement deposition on the rfhSP-D opsonised CNTs led to dampening of the pro-inflammatory immune response. Furthermore, like CNTs, Iron oxide nanoparticles are also recognized by complement pathway, but mainly by alternative complement pathway. Complement deposition enhanced their uptake by activated THP-1 macrophages and dampened the pro-inflammatory responses. These studies emphasise the significance of understanding the interaction between innate immune humoral factors including complement in developing nanoparticle-based drug delivery strategies.
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