Immune plexins and semaphorins: old proteins, new immune functions

Plexins and semaphorins are a large family of proteins that are involved in cell movement and response. The importance of plexins and semaphorins has been emphasized by their discovery in many organ systems including the nervous (Nkyimbeng-Takwi and Chapoval, 2011; McCormick and Leipzig, 2012; Yaron and Sprinzak, 2012), epithelial (Miao et al., 1999; Fujii et al., 2002), and immune systems (Takamatsu and Kumanogoh, 2012) as well as diverse cell processes including angiogenesis (Serini et al., 2009; Sakurai et al., 2012), embryogenesis (Perala et al., 2012), and cancer (Potiron et al., 2009; Micucci et al., 2010). Plexins and semaphorins are transmembrane proteins that share a conserved extracellular semaphorin domain (Hota and Buck, 2012). The plexins and semaphorins are divided into four and eight subfamilies respectively based on their structural homology. Semaphorins are relatively small proteins containing the extracellular semaphorin domain and short intra-cellular tails. Plexins contain the semaphorin domain and long intracellular tails (Hota and Buck, 2012). The majority of plexin and semaphorin research has focused on the nervous system, particularly the developing nervous system, where these proteins are found to mediate many common neuronal cell processes including cell movement, cytoskeletal rearrangement, and signal transduction (Choi et al., 2008; Takamatsu et al., 2010). Their roles in the immune system are the focus of this review

Pivotal role of matrix metalloproteinase 13 in extracellular matrix turnover in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by excessive deposition of extracellular matrix (ECM).We investigated the regulation of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in lung fibrosis.MMP and TIMP expression, collagenolytic activity and collagen content was assessed in IPF (n=16) versus donor (n=6) lung homogenates and accomplished by in-situ-zymography for gelatinolytic and collagenolytic activities, combined with MMP antigen detection. Role of MMP13 was assessed employing the bleomycin model of lung fibrosis in MMP-13(-/-) versus wild-type mice.In IPF, MMPs-1, 2, 7, 9 and 13, but not MMP-8, were significantly upregulated, whereas none of the TIMPs (1-4) were significantly altered. Collagen content was slightly increased and collagenolytic activity was most prominent in the airways and co-localized with MMP-13. We observed an exaggerated early inflammatory response and an augmented lung fibrosis in bleomycin-challenged MMP-13(-/-) versus wild-type mice, with elevated lung collagen content 28d after bleomycin challenge in the MMP-13(-/-) mice.Our data suggest that i) collagen deposition in IPF lungs is not primarily due to excessive TIMP production, but rather due to overwhelming ECM production in face of an overall increased, but spatially imbalanced collagenolytic activity, ii) preferential distribution of collagenolytic activity, largely MMP-13, in the airways offers an explanation for the development of honeycomb cysts and iii) despite an overall increase in inflammatory cell content the presence of MMP-13 seems to limit the overall extent of ECM deposition in lung fibrosis

Gelatinolytic activities in IPF versus donor (control) lungs.

<div><p>A–C: Representative zymogram of gelatin substrate zymography of homogenates of control and IPF lungs (A); lytic zones of MMP-2 and MMP-9 activity appear white over the dark background. Densitometric analysis of pro- and active-MMP-2 activity (B); and of pro- and active MMP-9 activity (C). **<i>p < 0.01</i> IPF compared with controls.</p> <p>D–G: Representative photomicrograph of H&E stain of cryo-sectioned IPF lung tissue (D) and (F), and gelatinase in situ zymography combined with immunohistochemistry for MMP-2 and MMP-9. MMP-2 antigen signal was dot-like in pattern, localized mostly to alveolar and luminal cells and co-localized with gelatinase activity in hyperplastic epithelia (E, G). MMP-9 antigen also showed a dot-like pattern of expression, localized both to the airways and lung parenchyma, and but with limited co-localization with gelatinase activity (g) (Blue = nuclei, green = gelatinolytic activity, red = MMP-2 antigen in (E) or MMP-9 antigen in (G). Original magnification = 10X, scale = 100µm.</p></div