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 (stroma) transforming growth factor-β dysregulations 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 monoctyes 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.

Objective Sjögren’s syndrome(SS) represents a chronic autoimmune disease of unknown etiology that targets salivary and lacrimal glands and may be accompanied by multi-organ systemic manifestations. To further an understanding of immunopathology associated with SS and uncover therapeutic targets, we compared gene expression profiles of salivary glands with severe inflammation to those with mild or no disease. Methods Using microarray profiling of salivary gland tissues from SS patients and controls, we identified target genes that were further characterized in tissues, serum and in cultured cell populations by real time PCR and protein analyses. Results Among the most highly expressed SS genes were genes associated with myeloid cells, including members of the mammalian chitinase family, not previously associated with exocrinopathies. Both chitinase-3-like-1(CHI3L1/YKL-40) and chitinase 1(CHIT1), highly conserved chitinase-like glycoproteins, one with and one lacking enzymatic activity, were evident at the transcriptome level, and detected within inflamed tissues. Chitinases are expressed during monocyte-to-macrophage differentiation, and augmented by cytokines, including IFNα. Conclusions Since elevated expression of these and other macrophage-derived molecules corresponded with more severe SS, these observations suggest potential immunopathologic macrophage involvement and furthermore, that the tissue macrophage transcriptional profile reflects multiple genes induced by IFNα.

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.