Regulated expression and function of TLRs in human disease

Toll-like receptors (TLRs) are a critical component of the innate immune system due to their ability to detect conserved pathogen associated molecular patterns. Activation of these receptors results in a variety of functions, including the secretion of cytokines and direct antimicrobial activity.;Initially, we examine the regulation of TLR2 and TLR1 expression and function in two inflammatory skin conditions: leprosy and psoriasis. We demonstrate that TLR2 and TLRI are more highly expressed in the self healing tuberculoid form as compared to the disseminated lepromatous form. In addition, the type 1 cytokines found in tuberculoid lesions upregulated TLR2 expression and function whereas the type 2 cytokines prominent in lepromatous are suppressive. Similarly, TLR5 and TLR9 are highly expressed in psoriatic lesions, and both their expression and function can be upregulated by TGFα, a cytokine expressed at high levels in psoriasis. We also show that a therapeutic agent used to treat inflammatory acne can downregulate TLR2 and TLR1 expression and function as well.;Next, we investigated the role of TLR activation in the mediation of host defense. We show that TLR2/1 activation leads to monocytic differentiation into two distinct populations of macrophages and dendritic cells, two innate cell types. The macrophages have superior phagocytic ability, and the dendritic cells are more capable in cytokine secretion and antigen presentation. Finally, we investigate the ability of macrophages and dendritic cells to induce direct antimicrobial activity after TLR stimulation. Mycobaterium tuberculosis infected macrophages have microbicidal activity following TLR2/1 stimulation and dendritic cells do not. Using gene expression profiling, we show that this TLR2/1 mediated antimicrobial activity is vitamin D receptor (VDR) dependent.;The data presented in this thesis demonstrate that TLRs are critical components to human host defense. They are present at the site of disease and their expression and function can be regulated by the local cytokines or even therapeutic agents. Activation of TLRs induce differentiation of macrophages and dendritic cells, both which are critical for host defense. Finally, we demonstrate that the TLR-induced antimicrobial activity is mediated through VDR and that the serum levels of vitamin D prohormone are critical for mounting appropriate host defense mechanisms.