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ABSTRACT: The role of matricellular proteins in bacterial containment and in the induction of pathogen-specific adaptive immune responses is unknown. We studied the function of the matricellular protein secreted protein, acidic and rich in cysteine (SPARC/osteonectin) in the dissemination of locally injected Salmonella typhimurium and in the subsequent immune response. We show that SPARC was required for the development of organized acute inflammatory reactions with granuloma-like (GL) features and for the control of bacterial spreading to draining lymph nodes (DLNs). However, SPARC-related GL also inhibited dendritic cell (DC) migration to the DLNs and limited the development of adaptive immune response, thus conferring increased susceptibility to the pathogen. In SPARC-deficient mice, both DC migration and antigen-specific responses were restored against bacteria, leading to protective anti-S. typhimurium immunity. This highlights a new function of matricellular proteins in bacterial infection and suggests that initial containment of bacteria can have drawbacks.
Journal of Experimental Medicine 04/2008; 205(3):657-67. · 13.85 Impact Factor
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ABSTRACT: On their path to draining lymph nodes, epidermal Langerhans cells traverse collagen-dense connective tissue before reaching lymphatic vessels. The matricellular protein SPARC (secreted protein, acidic and rich in cysteine), which is induced during inflammation and tissue repair, organizes collagen deposition in tissue stroma. We analyzed Langerhans cell and dendritic-cell migration and its impact on T-cell priming in SPARC-null (SPARC(-/-)) and SPARC-sufficient (SPARC(+/+)) mice. Although the same number of Langerhans cells populate the ear skin of SPARC(-/-) and SPARC(+/+) mice, more Langerhans cells were found in the lymph nodes draining antigen-sensitized ears of SPARC(-/-) mice and significantly more Langerhans cells migrated from null-mice-derived ear skin explants. Such favored Langerhans cell migration is due to the host environment, as demonstrated by SPARC(+/+)>SPARC(-/-) and reciprocal chimeras, and have a profound influence on T-cell priming. Contact-, delayed type-hypersensitivity and naive T-cell receptor-transgenic T-cell priming, together indicate that the lack of SPARC in the environment accelerates the onset of T-cell priming by hastening Langerhans cell/dendritic-cell migration.
Journal of Cell Science 08/2005; 118(Pt 16):3685-94. · 6.11 Impact Factor
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ABSTRACT: Monocytes can develop into dendritic cells (DCs) that migrate to lymph nodes (LNs) and present antigens to T cells. However, we find that this differentiation is blocked when monocytes accumulate subcutaneously in response to bacteria or lipopolysaccharide (LPS). The inhibition of DC differentiation is mediated by the bacteria and in conjunction with inflammatory cells recruited at the site of injection. Inhibition of migratory DC development was reversed in Toll-like receptor (TLR)4-mutated mice when LPS, but not whole bacteria, was injected, suggesting that TLR4 is one but not the only mediator of the inhibition. The block imposed by bacteria was partly relieved by the absence of interleukin (IL)-12 p40, but not by individual absence of several cytokines involved in DC differentiation or in inflammation, i.e., IL-6, IL-10, IL-12 p35, and interferon gamma. Consistent with the inability of monocytes to yield migrating DCs, and the finding that other DCs had limited access to particulate or bacterial antigens, these antigens were weakly presented to T cells in the draining LN. These results illustrate that bacteria-associated signals can have a negative regulatory role on adaptive immunity and that local innate responses for containment of infectious bacteria can at least initially supersede development of adaptive responses.
Journal of Experimental Medicine 10/2003; 198(8):1253-63. · 13.85 Impact Factor
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ABSTRACT: Toll-like receptor 4 (TLR4) has been recently associated with cellular responses to lipopolysaccharide (LPS), and mice mutated in tlr4, such as C57BL/10ScCr or C3H/HeJ mice, become hyporesponsive to LPS. In this study, we have analyzed the capacity of bone marrow-derived dendritic cells (BMDC) from C57BL/10ScCr (ScCr-BMDC) or C3H/HeJ (HeJ-BMDC) mice to respond to LPS or to Gram-negative bacteria. We show that ScCr- or HeJ-BMDC are insensitive to LPS, but can mature in response to live and killed Gram-negative bacteria. Interestingly, only ScCr-BMDC but not HeJ-BMDC, stimulated with bacteria, have reduced capacity to produce pro- and anti-inflammatory cytokines as compared to BMDC from control mice, probably due to genetic defects unrelated to the tlr4 mutation. Nevertheless, ScCr-BMDC and ScCr BM-macrophages (BM-Mphi) phagocytose Salmonella typhimurium similarly to control cells, indicating that TLR4 is not compulsory for bacterial uptake. Moreover, BM-Mphi, but not BM-DC from B10ScCr or C3H/HeJ mice, are impaired in their capacity to kill intracellular bacteria and to produce NO as compared to wild type controls. However, the bacteria killing property of BM-Mphi is completely restored by pretreating the cells with IFN-gamma. Hence, TLR4 plays different roles in DC versus Mphi.
European Journal of Immunology 11/2002; 32(10):2800-6. · 5.10 Impact Factor
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ABSTRACT: Penetration of the gut mucosa by pathogens expressing invasion genes is believed to occur mainly through specialized epithelial cells, called M cells, that are located in Peyer's patches. However, Salmonella typhimurium that are deficient in invasion genes encoded by Salmonella pathogenicity island 1 (SPI1) are still able to reach the spleen after oral administration. This suggests the existence of an alternative route for bacterial invasion, one that is independent of M cells. We report here a new mechanism for bacterial uptake in the mucosa tissues that is mediated by dendritic cells (DCs). DCs open the tight junctions between epithelial cells, send dendrites outside the epithelium and directly sample bacteria. In addition, because DCs express tight-junction proteins such as occludin, claudin 1 and zonula occludens 1, the integrity of the epithelial barrier is preserved.
Nature Immunology 03/2001; 2(4):361-367. · 26.01 Impact Factor
