Receptor-Interacting Protein-2 Deficiency Delays Macrophage Migration and Increases Intracellular Infection during Peritoneal Dialysis-Associated Peritonitis

McCully, Michelle L.; Fairhead, Todd; Colmont, Chantal Sophie; Beasley, Federico C.; Heinrichs, David E.; Blake, Peter G.; Topley, Nicholas; Madrenas, Joaquı́n

doi:10.1159/000141041

Cited by 9 publications

(5 citation statements)

References 90 publications

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“…However, even the larger numbers of leukocytes were unable to resolve OM in a timely manner. While a previous study of RIP2-deficient peritoneal macrophages showed reduced intracellular killing of Staphylococcus aureus (McCully et al, 2008), we did not see a defect in either NTHi phagocytosis or killing by RIP2 −/− macrophages (Figure 7). At least for macrophages, defects in their ability to clear bacteria could not explain the deficit in OM resolution.…”

Section: Discussioncontrasting

confidence: 92%

“…Of note our gene array date indicate that Tlr2 is strongly upregulated (Leichtle et al, 2022), which may have a potential role in RIP2 activation (Kobayashi et al, 2002). While RIP2-mediated responses to infection have been observed in leukocytes at other sites (McCully et al, 2008;Shimada et al, 2018;Honjo et al, 2021), in the ME Ripk2 and Nod gene expression was prominent only in epithelial and stromal cells (Figure 4). These cells are thus the most likely to be contributors to RIP2-mediated responses during OM.…”

Section: Discussionmentioning

confidence: 83%

“…While RIP2-mediated responses to infection have been observed in leukocytes at other sites ( McCully et al, 2008 ; Shimada et al, 2018 ; Honjo et al, 2021 ), in the ME Ripk2 and Nod gene expression was prominent only in epithelial and stromal cells ( Figure 4 ). These cells are thus the most likely to be contributors to RIP2-mediated responses during OM.…”

Section: Discussionmentioning

confidence: 87%

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Essential Role of the Innate Immune Adaptor RIP2 in the Response to Otitis Media

et al. 2022

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Intracellular nucleotide binding and oligomerization domain (NOD) and Toll-like (TLR) receptors have emerged as pivotal sensors of infection. Both Nod1 and Nod2 contain a caspase activation and recruitment domain (CARD) that interacts with the adaptor protein RIP2 (receptor-interaction protein-2). This leads to ubiquitination of RIP2 and in turn to the activation of NFκB and MAPK transcription factors, to command the host defensive response against pathogenic infections. RIP2 is also activated by TLRs 2 and 4, although the mechanism of this activation is less. The role of RIP2 in otitis media (OM) pathogenesis has yet to be examined. Herein, we used in vivo animal models including C57BL/6 wild-type (WT) and RIP2−/− knockout mice inoculated in the middle ear (ME) with non-typeable Haemophilus influenzae (NTHi), a common human OM pathogen, to evaluate the expression of RIP2 and its signaling genes at the cellular level to determine the role of RIP2 in OM pathogenesis and recovery. The Nod1, Nod2, and Ripk2 genes are minimally expressed in the normal ME. However, they are strongly upregulated during acute OM, as are many genes related to RIP2 signaling. However, while signaling genes were expressed by various ME cell types, only mucosal epithelial and stromal cells expressed the NODs, RIP2, and signaling genes required for the activation of the host defensive response. Whereas WT mice clear ME bacteria and recover from OM within 5 days after infection, RIP2-deficient mice show persistent ME bacterial carriage and inflammation to at least 15 days. This includes significantly prolonged mucosal hyperplasia and ME leukocytic infiltration. Recruitment of macrophages is also delayed in comparison to WT mice. Thus, RIP2 is required to elicit a robust innate immune response that promotes bacterial clearance and increases host innate resistance. The results also identify the structural cells of the ME mucosa, as opposed to leukocytes, as the primary sites of NOD/RIP2 activity in the infected ME.

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Section: Discussioncontrasting

confidence: 92%

Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 87%

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Essential Role of the Innate Immune Adaptor RIP2 in the Response to Otitis Media

et al. 2022

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“…Nod proteins mediate host defense against a variety of both Gram negative and Gram positive bacteria. For example, Nod2 senses the PGN produced by Staphylococcus aureus , and Rip2 limits S. aureus growth in macrophages [51]. Also, Nod2 detects the MDP structure found in almost all bacteria [37].…”

Section: Discussionmentioning

confidence: 99%

The NOD/RIP2 Pathway Is Essential for Host Defenses Against Chlamydophila pneumoniae Lung Infection

et al. 2009

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Here we investigated the role of the Nod/Rip2 pathway in host responses to Chlamydophila pneumoniae–induced pneumonia in mice. Rip2−/− mice infected with C. pneumoniae exhibited impaired iNOS expression and NO production, and delayed neutrophil recruitment to the lungs. Levels of IL-6 and IFN-γ levels as well as KC and MIP-2 levels in bronchoalveolar lavage fluid (BALF) were significantly decreased in Rip2−/− mice compared to wild-type (WT) mice at day 3. Rip2−/− mice showed significant delay in bacterial clearance from the lungs and developed more severe and chronic lung inflammation that continued even on day 35 and led to increased mortality, whereas WT mice cleared the bacterial load, recovered from acute pneumonia, and survived. Both Nod1−/− and Nod2−/− mice also showed delayed bacterial clearance, suggesting that C. pneumoniae is recognized by both of these intracellular receptors. Bone marrow chimera experiments demonstrated that Rip2 in BM-derived cells rather than non-hematopoietic stromal cells played a key role in host responses in the lungs and clearance of C. pneumoniae. Furthermore, adoptive transfer of WT macrophages intratracheally was able to rescue the bacterial clearance defect in Rip2−/− mice. These results demonstrate that in addition to the TLR/MyD88 pathway, the Nod/Rip2 signaling pathway also plays a significant role in intracellular recognition, innate immune host responses, and ultimately has a decisive impact on clearance of C. pneumoniae from the lungs and survival of the infectious challenge.

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“…The NOD pathway also protects the host against Chlamydophila pneumoniae [44], Staphylococcus aureus [45], T. cruzi [46], Listeria monocytogenes [9], Helicobacter pilori [47], T. gondii [48], Escherichia coli [49] and…”

Section: Discussionmentioning

confidence: 99%

A sinalização via NOD2-RIP2 modula a imunidade adaptativa contra <i>Leishmania infantum</i>

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Receptor-Interacting Protein-2 Deficiency Delays Macrophage Migration and Increases Intracellular Infection during Peritoneal Dialysis-Associated Peritonitis

Cited by 9 publications

References 90 publications

Essential Role of the Innate Immune Adaptor RIP2 in the Response to Otitis Media

Essential Role of the Innate Immune Adaptor RIP2 in the Response to Otitis Media

The NOD/RIP2 Pathway Is Essential for Host Defenses Against Chlamydophila pneumoniae Lung Infection

A sinalização via NOD2-RIP2 modula a imunidade adaptativa contra <i>Leishmania infantum</i>

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