Simultaneously, these lipids inhibit the innate immune response against the bacteria through diminishing TLR-induced antimicrobial activity and skewing the cytokine balance to induce more IL-10 and less IL-12 cytokine production (Cruz et al

Simultaneously, these lipids inhibit the innate immune response against the bacteria through diminishing TLR-induced antimicrobial activity and skewing the cytokine balance to induce more IL-10 and less IL-12 cytokine production (Cruz et al., 2008). response, phagocytosis and antimicrobial responses, as being co-regulated for optimal host defense. Following phagocytosis, there are a variety of antimicrobial mechanisms that macrophages (M) utilize to kill pathogens, including the generation of nitric oxide and superoxide radicals, and in humans the vitamin D-dependent induction of antimicrobial peptides including cathelicidin (Liu et al., 2006). Although a key cytokine of the acquired immune system, IFN-, 3-TYP can both reduce phagocytosis (Backman and Guyre, 3-TYP 1994; Konopski et al., 1994) and is also known to upregulate antimicrobial activity, the mechanisms by which these pathways are regulated by the innate immune system are less clear. In addition to phagocytosis of microbial pathogens, M also have a scavenger function to remove extracellular material including apoptotic cells, cellular debris and toxic metabolic products (Mosser and Edwards, 2008). In 3-TYP particular, M phagocytosis of oxidized lipoproteins, such as oxidized low-density lipoprotein (oxLDL), maintains proper lipid homeostasis within tissues (Mosser and Edwards, 2008; Greaves and Gordon, 2008), but can lead to foam cell formation in a variety of chronic infectious and noninfectious inflammatory disorders including atherosclerosis (Li and Glass, 2002), 3-TYP Whipple disease (Desnues et al., 2006), xanthomas (Caputo et al., 1986), and mycobacterial diseases such as tuberculosis (Lucas, 1988; Hunter et al., 2007; Pagel, 1925; Virchow, 1860; Ridley and Ridley, 1987) and leprosy (Lucas, 1988; Virchow, 1863; Sakurai and Skinsnes, 1970). The ability of M to endocytose macromolecules and particles in their environment involves several distinct mechanisms including pinocytosis, receptor-mediated endocytosis and phagocytosis (Mosser and Edwards, 2008; Greaves and Gordon, 2008). The mechanisms which regulate these M antimicrobial and phagocytic functions are central to our understanding of innate immune responses against microbial pathogens. Leprosy provides an ideal model to study the human innate immune response to microbial contamination, BTLA since the disease forms a clinical spectrum in which the pathogen, infects M, and its fate correlates with the type of immune response (Yamamura et al., 1991). Although M infiltration is usually prominent in all lesions, M in the self-healing tuberculoid (T-lep) form are well-differentiated and rarely contain bacteria, whereas, M in the disseminated lepromatous (L-lep) form are characterized by abundant intracellular bacilli and foam cell formation as the result of the accumulation of host-and pathogen-derived lipids (Cruz et al., 2008). Cytokine patterns are also distinct, T-lep lesions express IFN-, TNF-, and IL-15, whereas, L-lep lesions are characterized by the expression of IL-4 and IL-10 (Jullien et al., 1997; Yamamura et al., 1991). Of these cytokines, IL-15 and IL-10 are both produced by activation of the innate immune system and are known to regulate M function, but are differentially expressed in leprosy lesions. The ability of IL-15 to induce M antimicrobial activity is usually consistent with the expression of this cytokine in self-limited T-lep lesions (Jullien et al., 1997); however the comparative effects of IL-10 on M function are not known. We therefore hypothesized that key cytokines of the innate immune system, IL-15 and IL-10, trigger distinct M functional programs with relevance to host defense in human infection. RESULTS IL-10 differentiates monocytes into CD209+CD163+ M To compare the ability of two key innate immune cytokines, IL-10 and IL-15, to trigger M functional programs (Sozzani et al., 1998; Krutzik et al., 2005), we cultured human peripheral blood monocytes with IL-10 or IL-15 for 2 days. Initially, we examined the expression of CD209, a C-type lectin receptor previously found to be expressed by tissue M and induced by IL-15 (Krutzik et.