Induction of p38 Mitogen-activated Protein Kinase Reduces Early Endosome Autoantigen 1 (EEA1) Recruitment to Phagosomal Membranes

Fratti, Rudtilio A.; Chua, Jennifer; Deretic, Vojo

doi:10.1074/jbc.m305225200

Cited by 100 publications

(101 citation statements)

References 40 publications

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“…49 Activation of p38 plays a role in EEA1 exclusion, an early endosomal protein, from M. tuberculosis phagosomes and in inhibiting the maturation of mycobacterial phagosomes. 44 Dependence of the survival of Brucella melitensis on p38 and JNK activation has also been reported. 50 Figure 4 COX-2 expression and PGE2 secretion by colon cancerassociated E. coli-infected macrophages.…”

Section: Discussionmentioning

confidence: 99%

“…It could be speculated that colon cancerassociated E. coli hijack the p38 MAPK signaling pathway to create an intracellular niche where they can survive and replicate. MAPKs are involved in membrane trafficking, and thus control key steps of phagolysosome biogenesis [44][45][46] and regulate autophagy pathway. 47,48 Some intracellular pathogens hijack MAPK signaling pathways in favor of their survival.…”

Section: Discussionmentioning

confidence: 99%

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Intracellular colon cancer-associated Escherichia coli promote protumoral activities of human macrophages by inducing sustained COX-2 expression

Raisch

Rolhion

Dubois

et al. 2015

Laboratory Investigation

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Intestinal dysbiosis has been reported in patients with colorectal cancer, and there is a high prevalence of Escherichia coli belonging to B2 phylogroup and producing a genotoxin, termed colibactin. Macrophages are one of the predominant tumor-infiltrating immune cells supporting key processes in tumor progression by producing protumoral factors such as cyclooxygenase-2 (COX-2). Here, we investigated whether B2 E. coli colonizing colon tumors could influence protumoral activities of macrophages. In contrast to commensal or nonpathogenic E. coli strains that were efficiently and rapidly degraded by macrophages at 24 h after infection, colon cancer-associated E. coli were able to resist killing by human THP-1 macrophages, to replicate intracellularly, and to persist inside host cells until at least 72 h after infection. Significant increases in COX-2 expression were observed in macrophages infected with colon cancer E. coli compared with macrophages infected with commensal and nonpathogenic E. coli strains or uninfected cells at 72 h after infection. Induction of COX-2 expression required live bacteria and was not due to colibactin production, as similar COX-2 levels were observed in macrophages infected with the wild-type colon cancer-associated E. coli 11G5 strain or a clbQ mutant unable to produce colibactin. Treatment of macrophages with ofloxacin, an antibiotic with intracellular tropism, efficiently decreased the number of intracellular bacteria and suppressed bacteria-induced COX-2 expression. This study provides new insights into the understanding of how tumor-infiltrating bacteria could influence cancer progression through their interaction with immune cells. Manipulation of microbes associated with tumors could have a deep influence on the secretion of protumoral molecules by infiltrating macrophages. Colorectal cancer (CRC) is one of the most commonly diagnosed malignancies worldwide, making it the fourth most common cause of cancer deaths throughout the world. 1 CRC is a heterogeneous disease, including at least three major forms: hereditary, sporadic, and colitis-associated CRC. A large body of evidence indicates that genetic mutations, epigenetic changes, chronic inflammation, diet, and lifestyle deeply affect CRC onset. 2,3 In addition to these factors, gut microbiota dysbiosis has been reported in CRC patients. [4][5][6][7][8][9] Recent pyrosequencing analysis of CRC-associated bacterial microbiota has revealed dysbiosis with, in particular, overrepresentation of Fusobacterium and Bacteroides. [10][11][12][13][14] In addition, our group and others have shown that colonic adenomas, carcinomas, and the mucosa of CRC patients are abnormally colonized by Escherichia coli belonging to the B2 phylogroup, with a high prevalence of E. coli producing a genotoxin, termed colibactin, encoded by the pks genomic island. [15][16][17][18][19][20] It has been recently demonstrated that cells that survive infection with colibactin-producing E. coli display hallmarks of cellular senescence accompanied with productio...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Intracellular colon cancer-associated Escherichia coli promote protumoral activities of human macrophages by inducing sustained COX-2 expression

Raisch

Rolhion

Dubois

et al. 2015

Laboratory Investigation

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“…Activation of the MAPK signaling pathway upon mycobacterial infection has been demonstrated to inhibit several antimicrobial mechanisms (13). Mycobacteria exploit p38 to arrest phagosome maturation in murine macrophages, and pharmacological blockade of p38 activity enhances phagosome acidi- fication (9). Moreover, activation of MAPK signaling by an M. tuberculosis 19-kDa lipoprotein has been demonstrated to inhibit class II transactivator and, as a consequence, class II MHC expression by murine macrophages (20).…”

Section: Discussionmentioning

confidence: 99%

Mycobacteria Exploit p38 Signaling To Affect CD1 Expression and Lipid Antigen Presentation by Human Dendritic Cells

et al. 2009

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Group I CD1 proteins are specialized antigen-presenting molecules that present both microbial and self lipid antigens to CD1-restricted ␣/␤ T lymphocytes. The production of high levels of gamma interferon and lysis of infected macrophages by lipid-specific T lymphocytes are believed to play pivotal roles mainly in the defense against mycobacterial infections. We previously demonstrated that Mycobacterium tuberculosis and bacillus Calmette-Guérin (Mycobacterium bovis BCG) induce human monocytes to differentiate into CD1 ؊ dendritic cells (DC), which cannot present lipid antigens to specific T cells. Here, we show that in human monocytes mycobacteria trigger phosphorylation of p38 mitogen-activated protein kinase to inhibit CD1 expression in DC derived from infected monocytes. Pretreatment with a specific p38 inhibitor renders monocytes insensitive to mycobacterial subversion and allows them to differentiate into CD1 ؉ DC, which are fully capable of presenting lipid antigens to specific T cells. We also report that one of the pathogen recognition receptors triggered by BCG to activate p38 is complement receptor 3 (CR3), as shown by reduced p38 phosphorylation and partial reestablishment of CD1 membrane expression obtained by CR3 blockade before infection. In conclusion, we propose that p38 signaling is a novel pathway exploited by mycobacteria to affect the expression of CD1 antigen-presenting cells and avoid immune recognition.

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“…hMDMs were fixed in PFA and washed three times. Staining of the lysosomal marker CD63, which is found on mature phagosomes (9), was performed in a humid chamber. Briefly, cells were blocked in blocking solution containing PBS with 2% bovine serum albumin and 10% normal goat serum and permeabilized (at RT for 30 min) in blocking solution supplemented with 0.1% (wt/vol) saponin.…”

Section: Methodsmentioning

confidence: 99%

Incorporation ofMycobacterium tuberculosisLipoarabinomannan into Macrophage Membrane Rafts Is a Prerequisite for the Phagosomal Maturation Block

et al. 2008

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Lipoarabinomannan (LAM) is one of the key virulence factors for Mycobacterium tuberculosis, the etiological agent of tuberculosis. During uptake of mycobacteria, LAM interacts with the cell membrane of the host macrophage and can be detected throughout the cell upon infection. LAM can inhibit phagosomal maturation as well as induce a proinflammatory response in bystander cells. The aim of this study was to investigate how LAM exerts its action on human macrophages. We show that LAM is incorporated into membrane rafts of the macrophage cell membrane via its glycosylphosphatidylinositol anchor and that incorporation of mannosecapped LAM from M. tuberculosis results in reduced phagosomal maturation. This is dependent on successful insertion of the glycosylphosphatidylinositol anchor. LAM does not, however, induce the phagosomal maturation block through activation of p38 mitogen-activated protein kinase, contradicting some previous suggestions.Mycobacterium tuberculosis, the etiological agent of tuberculosis, spreads by aerosol, mainly infecting alveolar macrophages, by which the bacterium is ingested (17). Through inhibition of macrophage functions, the bacterium modulates the host immune response (25). The best-characterized virulence factor of M. tuberculosis, lipoarabinomannan (LAM), is an abundant glycolipid, which is attached to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor and extends through the cell wall of the bacterium (5). During uptake of mycobacteria, LAM interacts with the cell membrane of the host macrophage via specific receptors, including the macrophage mannose receptor and complement receptor 3 (13,14,19), and can then be detected at multiple sites in the cell (27). The host cell exports LAM from the phagosome in an exocytosis-like manner, eliciting responses in bystander cells (1-3). The M. tuberculosis surface harbors mannose-capped LAM (ManLAM), whereas other, less pathogenic, mycobacteria contain LAM either with a phospho-myo-inositol cap (PILAM) or no cap (6). The type of capping and the presence of the GPI anchor is crucial for virulence (13,14). The effects of Man-LAM on the host cell are multiple, but the interference of ManLAM with phagosomal maturation is the best characterized (21) and has been demonstrated in murine and human macrophages (10,12,14).Studies on human lymphocytes showed that LAM localizes to membrane rafts of the lymphocyte membrane, thereby interfering with signaling affecting cytokine production (20).Membrane rafts are cholesterol-and glycosphingolipid-rich domains that act as platforms for cell signaling processes (16). The aim of this study was to investigate whether the effects of LAM are due to incorporation of LAM into membrane rafts of human macrophages. We establish that LAM is incorporated into membrane rafts of the macrophage cell membrane via its GPI anchor, resulting in reduced phagosomal maturation. MATERIALS AND METHODSAntigens and antibodies. ManLAM, cell wall fractions (CWF), and phosphatidylinositol mannosides (PIM) from the virulen...

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Induction of p38 Mitogen-activated Protein Kinase Reduces Early Endosome Autoantigen 1 (EEA1) Recruitment to Phagosomal Membranes

Cited by 100 publications

References 40 publications

Intracellular colon cancer-associated Escherichia coli promote protumoral activities of human macrophages by inducing sustained COX-2 expression

Intracellular colon cancer-associated Escherichia coli promote protumoral activities of human macrophages by inducing sustained COX-2 expression

Mycobacteria Exploit p38 Signaling To Affect CD1 Expression and Lipid Antigen Presentation by Human Dendritic Cells

Incorporation ofMycobacterium tuberculosisLipoarabinomannan into Macrophage Membrane Rafts Is a Prerequisite for the Phagosomal Maturation Block

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