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

Abstract

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.

RIP kinases: key decision makers in cell death and innate immunity

“…Thus RIP2-deficient mice show impaired bacterial clearance in an E. Coli pneumonia infection model 184 and Chlamydophila pneumoniae-induced pneumonia. 185 In both models, the absence of RIP2 resulted in impaired expression of various pro-inflammatory mediators, reduced neutrophil infiltration and increased bacterial burden. However, under certain circumstances, the role of RIP2 in mediating an antibacterial response can be damaging to the host.…”

Intracellular Pathogen Sensor NOD2 Programs Macrophages to Trigger Notch1 Activation

“…Importantly, a recent report suggests that infection of RIP2 null mice with Chlamydophila pneumoniae resulted in increased mortality due to a defect in generation of effective NO production. This clearly ascribes a significant and dominant role for NOD2/RIP2 signaling in induced expression of iNOS/NO, despite the presence of the intact TLR2 signaling module in RIP2-deficient mice or TLR2 agonists in C. pneumoniae (47). NO act as a crucial molecular signal during diverse pathophysiological conditions and NO/iNOS-mediated regulation of immunomodulatory gene expression involves multiple pathways in macrophages (22).…”

Immune Recognition in Lung Diseases: Basic Research and Clinical Application

“…NOD2 recognizes the muramyl dipeptide (MDP) which is conserved in peptidoglycans of positive and gram-negative bacteria. NOD2 senses S. pneumoniae, S. aureus, Escherichia coli, C. pneumoniae and M. tuberculosis [41][42][43]. NOD1 and NOD2 both activated downstream signaling through Rip2 kinase, leading to the expression, NFkB dependent, of pro-inflammatory mediators and the production of reactive oxygen species (ROS) [44].…”