Conserved bacterial components potently activate host immune cells through transmembrane Toll-like receptors (TLRs), which trigger a protective immune response but also may signal apoptosis. In this study, we investigated the roles of TLR2 and TLR4 as inducers of apoptosis in Yersinia enterocolitica-infected macrophages. Yersiniae suppress activation of the antiapoptotic NF-κB signaling pathway in host cells by inhibiting inhibitory κB kinase-β. This leads to macrophage apoptosis under infection conditions. Experiments with mouse macrophages deficient for TLR2, TLR4, or both receptors showed that, although yersiniae could activate signaling through both TLR2 and TLR4, loss of TLR4 solely diminished Yersinia-induced apoptosis. This suggests implication of TLR4, but not of TLR2, as a proapoptotic signal transducer in Yersinia-conferred cell death. In the same manner, agonist-specific activation of TLR4 efficiently mediated macrophage apoptosis in the presence of the proteasome inhibitor MG-132, an effect that was less pronounced for activation through TLR2. Furthermore, the extended stimulation of overexpressed TLR4 elicited cellular death in epithelial cells. A dominant-negative mutant of Fas-associated death domain protein could suppress TLR4-mediated cell death, which indicates that TLR4 may signal apoptosis through a Fas-associated death domain protein-dependent pathway. Together, these data show that TLR4 could act as a potent inducer of apoptosis in macrophages that encounter a bacterial pathogen.

Since the first description of Wohlfahrtiimonas chitiniclastica in 2008, a number of well described case reports demonstrating its pathogenic role in humans have been published. Infections may be closely linked to flies, such as Wohlfahrtia magnifica, Lucilia sericata, Chrysomya megacephala or Musca domestica. These insects are potent vectors for the distribution of W. chitiniclastica causing local or systemic infections originating from wounds infested with fly larvae. However, other potential sources of transmission of W. chitiniclastica have been described such as soil or chicken meat. Infections in humans reported to date comprise wound infections, cellulitis, osteomyelitis and sepsis. This review summarizes all the literature available up to now and gives the current knowledge about this emerging human pathogen. Additionally, four patients with proven W. chitiniclastica infections treated at Dresden University Hospital between 2013 and 2015, are included. Special focus was placed on microbiological identification and antibiotic susceptibility testing of the pathogen.

The induction of apoptosis in host cells is a common strategy by which pathogenic bacteria interfere with the host immune response. The Yersinia enterocolitica outer protein P (YopP) inhibits activation of transcription factor NF-κB in macrophages, which suppresses NF-κB-dependent antiapoptotic activities. The simultaneous initiation of proapoptotic signaling by yersiniae infection or LPS treatment results in macrophage apoptosis. In this study, we used YopP as a tool to dissect survival- and death-inducing pathways in bacteria-faced macrophages. We cotransfected J774A.1 macrophages with expression plasmids for YopP and dominant-negative mutants of signal transmitters of the NF-κB cascade downstream from the LPS receptor complex. Dominant-negative myeloid differentiation factor 88 (MyD88) or IL-1R-associated kinase (IRAK) 2 diminished LPS-induced apoptosis in YopP-transfected macrophages, suggesting implication of MyD88 and IRAK2 in signaling cell death. In contrast, dominant-negative IRAK1 and TNFR-associated factor 6 (TRAF6) did not provide protection, but augmented LPS-mediated apoptosis in the absence of YopP, which indicates roles of IRAK1 and TRAF6 in the antiapoptotic signal relay of the NF-κB cascade. The distinct functions of IRAK members in macrophage survival were reflected by opposing effects of dominant-negative IRAK1 and IRAK2 on Y. enterocolitica-mediated apoptosis. Yersiniae- and LPS-dependent cell death were substantially attenuated by a specific caspase-8 inhibitory peptide or by dominant negative Fas-associated death domain protein (FADD). This suggests, that Yersinia-induced apoptosis involves a proapoptotic signal relay through MyD88 and IRAK2, which potentially targets the Fas-associated death domain protein/caspase-8 apoptotic pathway, whereas IRAK1 and TRAF6 counteract the bacteria-induced cytotoxic response by signaling macrophage survival.

Multiple myeloma (MM) has been suggested to be associated with different neoplasms. Of 589 consecutive patients with MM, 59 (10%) had different neoplasms: solid tumors in 78% and hematological neoplasms in 22%. Different neoplasms were separated into those emerging prior or synchronously (p/s; n = 41) versus subsequently after the MM (n = 18). The rate of different neoplasms at the time of MM diagnosis was estimated as 6.6%, and estimated different neoplasm rates at 2, 5, and 10 years were 7.8%, 10.3%, and 11.6%, respectively. Patients with MM with p/s different neoplasms showed a hazard ratio (HR) for impaired overall survival of 1.2 (95% CI 0.8-2.0), whereas in those with subsequent neoplasms the HR was 2.5 (95% CI 1.4-4.4). This demonstrates that (1) p/s are more frequent compared with subsequent different neoplasms, and (2) the prognosis is more impaired with subsequent different neoplasms. Age ≥60 years was a confounding covariable with a HR of 2.021 (95% CI 1.6-2.6).

CCL18 and CXCL12 are homeostatic chemokines with high constitutive concentrations in serum. Elevated levels of CCL18 have been described in various diseases including childhood acute lymphocytic leukemia (ALL) but its functions remain poorly characterized. Its receptor has not been identified, but functional cellular responses like lymphocyte chemotaxis have been described. CXCL12 is a pivotal chemokine for hematopoiesis and B cell homing processes. We demonstrate that CCL18 interferes with CXCL12-mediated pre-B ALL cell activation. CXCL12-induced calcium mobilization, chemotaxis, pseudo-emperipolesis and cellular proliferation could be significantly reduced by CCL18 in pre-B ALL cell lines. The results could be observed in primary cells from patients suffering from pre-B ALL, but not in cells from patients suffering from common ALL. Direct effects of CCL18 on the receptor for CXCL12, CXCR4, could be excluded. Moreover, we found that CCL18 modulations of CXCL12-induced responses are mediated through the chemokine-like receptor GPR30. CCL18 bound to GPR30 expressing cells, and antibodies against GPR30 abolished this binding as well as CCL18-mediated functional effects. We also observed that, CCL18 interferes with the activation of GPR30 by previously identified ligands (17β-estradiol and chemical agonists). We therefore suggest that CCL18 is an important modulator of CXCR4-dependent responses in pre-B ALL cells via interactions with GPR30.