Modulation of Innate Host Factors by Mycobacterium avium Complex in Human Macrophages Includes Interleukin 17
ABSTRACT Background. Although opportunistic infections due to Mycobacterium avium complex (MAC) have been less common since the introduction of highly active antiretroviral therapy, globally, human immunodeficiency virus-1 (HIV-1)-positive patients remain predisposed to these infections. Absence of a properly functioning acquired immune response allows MAC persistence within macrophages localized in lymph nodes coinfected with HIV and MAC. Although a deficiency in interferon γ appears to play a part in the ability of MAC to deflect the macrophage-associated antimicrobial attack, questions about this process remain. Our study examines the ability of MAC to regulate interleukin 17 (IL-17), a proinflammatory cytokine involved in host cell recruitment. Methods. Coinfected lymph nodes were examined for IL-17 by immunohistochemical analysis. In vitro, macrophages exposed to mycobacteria were evaluated for transcription activities, proteins, and signaling pathways responsible for IL-17 expression. Infected macrophages were also analyzed for expression of interleukin 21 (IL-21) and negative regulators of immune responses. Results. Infection of macrophages triggered synthesis of IL-17, correlating with IL-17 expression by macrophages in coinfected lymph nodes. Infected macrophages exposed to exogenous IL-17 expressed CXCL10, which favors recruitment of new macrophages as targets for infection. Blockade of nuclear factor κ-light-chain-enhancer of activated B cells and mitogen-activated protein kinase pathways suppressed mycobacteria-induced IL-17 expression. MAC triggered expression of IL-21, IRF4, and STAT3 genes related to IL-17 regulation, as well as expression of the negative immunoregulators CD274(PD-L1) and suppressors of cytokine signaling. Conclusions. MAC-infected macrophages can provide an alternative source for IL-17 that favors accumulation of new targets for perpetuating bacterial and viral infection while suppressing host antimicrobial immune responses.
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ABSTRACT: The pathology of age-related macular degeneration (AMD) is characterized by degeneration of photoreceptors and retinal pigment epithelial cells as well as by changes of choroidal capillaries in the macula. Although AMD is not a typical uveitis, there is a consistence and an imbalance of ocular para-inflammation. Ocular inflammation, particularly in the macula, plays a critical role in AMD pathogenesis. The inflammatory and immune-related elements involved in AMD include inflammatory and related cells as well as the secreted molecules and factors from these cells. Innate immune system elements such as macrophages and cytokines play an important role in AMD pathology and pathogenesis. This chapter reviews the observed deviation in macrophage plasticity and the elevated expression of interleukin-17 in AMD eyes while discussing potential contributions to AMD pathogenesis. Targeting of these specific inflammatory pathways and molecules at appropriate times should be explored and may become promising novel adjunct agents to AMD therapy.Advances in Experimental Medicine and Biology 01/2014; 801:193-8. DOI:10.1007/978-1-4614-3209-8_25 · 2.01 Impact Factor