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The immunocompromised individual remains at risk for opportunistic infections, including Mycobacterium avium complex (MAC), most evident in individuals infected with human immunodeficiency virus-1 (HIV-1) [1–4]. Although infection with opportunistic pathogens represented an early diagnostic feature of AIDS, the nature of such opportunistic infections has changed over the past 2 decades with the use of highly active antiretroviral therapy (HAART) [5]. However, viral resistance and noncompliance with HAART can contribute to the prevalence of opportunistic infections that are associated with morbidity and mortality in patients with advanced AIDS [3]. In these patients. MAC has a predilection for the gastrointestinal tract and for lymphoid tissues and may disseminate via the bloodstream [1, 3, 4]. Of interest, immune reconstitution inflammatory syndrome, a transient focal manifestation of variable duration that begins after the initiation of HAART and reactivates preexisting infections, such as those due to MAC, has been increasingly reported in HIV-infected individuals [4, 6]. The introduction of tumor necrosis factor α (TNF-α) blockers in the treatment of autoimmune diseases has also led to an increased risk of infection and reactivation of infection due to various mycobacterial species, with MAC responsible for most pulmonary nontuberculous mycobacterial and disseminated infections [7]. In some patients receiving anti–TNF-α therapy, pulmonary nontuberculous mycobacterial disease developed even when therapy was administered with antimycobacterial drugs. Individuals with genetic defects in interferon γ (IFN-γ) and interleukin 12 (IL-12) signaling pathways, as well as elderly individuals, are also susceptible to MAC [8, 9]. Two severe cases of MAC infection, one of which was fatal, have been reported in a new immunodeficiency syndrome associated with CXCR4 dysfunction [10]. More recently, and for reasons that are still being studied, an increase in the number of nontuberculous MAC infections in non–HIV-infected individuals has become more evident [11]. Macrophages are essential in controlling MAC infection but can become infected with substantial numbers of MAC organisms when the level of IFN-γ–producing CD4+ T cells decreases, which is typical in patients with AIDS [1]. Moreover, macrophages infected with mycobacteria can become refractory to IFN-γ in vitro, and evidence suggests that therapeutic administration of exogenous IFN-γ may not always resolve MAC coinfections, even in the presence of HAART [12]. We recently showed that macrophage IFN-γ unresponsiveness is due, at least in part, to the ability of MAC to induce suppressors of cytokine signaling (SOCS) and that coinfected lymph nodes express high levels of SOCS1 and SOCS3 proteins [13]. To delineate factors that may influence recruitment of macrophage hosts to the site of mycobacterial replication, we examined the potential role of interleukin 17A (IL-17A), which is recognized as pivotal, particularly in the early response to infection [14]. IL-17 has been mostly linked to the CD4+ helper T-cell 17 (Th17) lineage and is also produced by γδ T cells, natural killer cells, neutrophils, and Paneth cells [14]. IL-17 is not only involved in initiating and sustaining the inflammatory response, it also plays critical roles in chronic inflammation and autoimmunity [15]. The IL-17 family of cytokines consists of 6 members, IL-17A–IL-17F, but their individual roles in infectious diseases are poorly defined [14]. Here, we provide evidence that IL-17 is involved in the host immune response to MAC but that increased IL-17 originates in macrophages localized in coinfected lymph nodes of patients with AIDS and is detected in macrophages infected in vitro. MAC-induced IL-17, in turn, may recruit new bacterial hosts, even in the relative absence of IFN-producing T cells, by inducing chemokines, such as CXCL10, associated with disease progression in MAC-infected patients [16]. Our data demonstrate involvement of the nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways in the regulation of MAC-induced IL-17 transcription. Exposure of macrophages to mycobacteria resulted in modulation of additional factors involved in regulation of IL-17 expression. On the other hand, enhanced expression of SOCS and CD274/PD-L1 may support an immunosuppressive environment favoring bacterial survival. MAC-induced IL-17 apparently triggers and sustains infiltration during the early and chronic immune response to mycobacteria, ensuring abundant target cells for both viral and mycobacterial replication, while dampening protective host-pathogen responses. Collectively, our data implicate MAC as modulating the immune response for its own benefit, thereby contributing to persistence of this opportunistic pathogen in the immunocompromised host.

Macrophages in the gastrointestinal mucosa represent the largest pool of tissue macrophages in the body. In order to maintain mucosal homeostasis, resident intestinal macrophages uniquely do not express the lipopolysaccharide (LPS) co-receptor CD14 or the IgA (CD89) and IgG (CD16, 32, and 64) receptors, yet prominently display Toll-like receptors (TLRs) 3-9. Remarkably, intestinal macrophages also do not produce proinflammatory cytokines in response to TLR ligands, likely because of extracellular matrix (stromal) transforming growth factor-β (TGF-β) dysregulation of nuclear factor (NF)-κB signal proteins and, via Smad signaling, expression of IκBα, thereby inhibiting NF-κB-mediated activities. Thus, in noninflamed mucosa, resident macrophages are inflammation anergic but retain avid scavenger and host defense function, an ideal profile for macrophages in close proximity to gut microbiota. In the event of impaired epithelial integrity during intestinal infection or inflammation, however, blood monocytes also accumulate in the lamina propria and actively pursue invading microorganisms through uptake and degradation of the organism and release of inflammatory mediators. Consequently, resident intestinal macrophages are inflammation adverse, but when the need arises, they receive assistance from newly recruited circulating monocytes.

Sjogren's syndrome is an autoimmune disease that targets exocrine glands, but often exhibits systemic manifestations. Infiltration of the salivary and lacrimal glands by lymphoid and myeloid cells orchestrates a perpetuating immune response leading to exocrine gland damage and dysfunction. Th1 and Th17 lymphocyte populations and their products recruit additional lymphocytes, including B cells, but also large numbers of macrophages, which accumulate with disease progression. In addition to cytokines, chemokines, chitinases, and lipid mediators, macrophages contribute to a proteolytic milieu, underlying tissue destruction, inappropriate repair, and compromised glandular functions. Among the proteases enhanced in this local environment are matrix metalloproteases (MMP) and plasmin, generated by plasminogen activation, dependent upon plasminogen activators, such as tissue plasminogen activator (tPA). Not previously associated with salivary gland pathology, our evidence implicates enhanced tPA in the context of inflamed salivary glands revolving around lymphocyte-mediated activation of macrophages. Tracking down the mechanism of macrophage plasmin activation, the cytokines IFNγ and to a lesser extent, IFNα, via Janus kinase (JAK) and signal transducer and activator of transcription (STAT) activation, were found to be pivotal for driving the plasmin cascade of proteolytic events culminating in perpetuation of the inflammation and tissue damage, and suggesting intervention strategies to blunt irreversible tissue destruction.

Differential expression of secretory leukocyte protease inhibitor (SLPI) impacts on tumor progression. SLPI directly inhibits elastase and other serine proteases, and regulates matrix metalloproteinases, plasminogen activation, and plasmin downstream targets to influence invasion. We examined tissues from human oral squamous cell carcinoma (OSCC) for SLPI expression in parallel with proteases associated with tumor progression and evaluated their relationships using tumor cell lines. Significantly decreased SLPI was detected in OSCC compared to normal oral epithelium. Furthermore, an inverse correlation between SLPI and histological parameters associated with tumor progression, including stage of invasion, pattern of invasion, invasive cell grade, and composite histological tumor score was evident. Conversely, elevated plasmin and elastase were positively correlated with histological parameters of tumor invasion. In addition to its known inhibition of elastase, we identify SLPI as a novel inhibitor of plasminogen activation through its interaction with annexin A2 with concomitant reduced plasmin generation by macrophages and OSCC cell lines. In an in vitro assay measuring invasive activity, SLPI blocked protease-dependent tumor cell migration. Our data suggest that SLPI may possess antitumorigenic activity by virtue of its ability to interfere with multiple requisite proteolytic steps underlying tumor cell invasion and may provide insight into potential stratification of oral cancer according to risk of occult metastasis, guiding treatment strategies.

Sjögren's syndrome (SS) is a chronic autoimmune disease of unknown etiology that targets salivary and lacrimal glands and may be accompanied by multiorgan systemic manifestations. To further the understanding of immunopathology associated with SS and identify potential therapeutic targets, we undertook the present study comparing the gene expression profiles of salivary glands with severe inflammation versus those of salivary glands with mild or no disease.Using microarray profiling of salivary gland tissue from patients with SS and control subjects, we identified target genes, which were further characterized in tissue, serum, and cultured cell populations by real-time polymerase chain reaction and protein analysis.Among the most highly expressed SS genes were those associated with myeloid cells, including members of the mammalian chitinase family, which had not previously been shown to be associated with exocrinopathies. Both chitinase 3-like protein 1 and chitinase 1, highly conserved chitinase-like glycoproteins (one with enzymatic activity and one lacking enzymatic activity), were evident at the transcriptome level and were detected within inflamed tissue. Chitinases were expressed during monocyte-to-macrophage differentiation and their levels augmented by stimulation with cytokines, including interferon-α (IFNα).Because elevated expression of these and other macrophage-derived molecules corresponded with more severe SS, the present observations suggest that macrophages have potential immunopathologic involvement in SS and that the tissue macrophage transcription profile reflects multiple genes induced by IFNα.