Modulation of Innate Host Factors by Mycobacterium avium Complex in Human Macrophages Includes Interleukin 17
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.
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.
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.
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.
Available from: Chi-Chao Chan
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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 03/2014; 801:193-8. DOI:10.1007/978-1-4614-3209-8_25 · 1.96 Impact Factor
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ABSTRACT: In the 2 decades since its discovery, IL-17A has become appreciated for mounting robust, protective responses against bacterial and fungal pathogens. When improperly regulated, however, IL-17A can play a profoundly pathogenic role in perpetuating inflammation and has been linked to a wide variety of debilitating diseases. IL-17A is often present in a composite milieu that includes cytokines produced by TH17 cells (i.e., IL-17F, IL-21, IL-22, and IL-26) or associated with other T cell lineages (e.g., IFN-γ). These combinatorial effects add mechanistic complexity and more importantly, contribute differentially to disease outcome. Whereas TH17 cells are among the best-understood cell types that secrete IL-17A, they are frequently neither the earliest nor dominant producers. Indeed, non-TH17 cell sources of IL-17A can dramatically alter the course and severity of inflammatory episodes. The dissection of the temporal regulation of TH17-associated cytokines and the resulting net signaling outcomes will be critical toward understanding the increasingly intricate role of IL-17A and TH17-associated cytokines in disease, informing our therapeutic decisions. Herein, we discuss important non-TH17 cell sources of IL-17A and other TH17-associated cytokines relevant to inflammatory events in mucosal tissues.
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Journal of Leukocyte Biology 12/2014; 97(3). DOI:10.1189/jlb.3RU0814-386R · 4.29 Impact Factor
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