Abstract
Intracellular pathogen sensor, NOD2, has been implicated in regulation of wide range of anti-inflammatory responses critical during development of a diverse array of inflammatory diseases; however, underlying molecular details are still imprecisely understood. In this study, we demonstrate that NOD2 programs macrophages to trigger Notch1 signaling. Signaling perturbations or genetic approaches suggest signaling integration through cross-talk between Notch1-PI3K during the NOD2-triggered expression of a multitude of immunological parameters including COX-2/PGE(2) and IL-10. NOD2 stimulation enhanced active recruitment of CSL/RBP-Jk on the COX-2 promoter in vivo. Intriguingly, nitric oxide assumes critical importance in NOD2-mediated activation of Notch1 signaling as iNOS(-/-) macrophages exhibited compromised ability to execute NOD2-triggered Notch1 signaling responses. Correlative evidence demonstrates that this mechanism operates in vivo in brain and splenocytes derived from wild type, but not from iNOS(-/-) mice. Importantly, NOD2-driven activation of the Notch1-PI3K signaling axis contributes to its capacity to impart survival of macrophages against TNF-α or IFN-γ-mediated apoptosis and resolution of inflammation. Current investigation identifies Notch1-PI3K as signaling cohorts involved in the NOD2-triggered expression of a battery of genes associated with anti-inflammatory functions. These findings serve as a paradigm to understand the pathogenesis of NOD2-associated inflammatory diseases and clearly pave a way toward development of novel therapeutics.
Highlights
Events regulating the activity of macrophages in terms of cytokine or chemokine production, receptor expression, and directed migration to secondary lymphoid organs for subsequent antigen presentation [2]
SiRNA-mediated knockdown of NOD2, receptor-interacting protein 2 (RIP2), or transforming growth factor--activated kinase 1 (TAK1) severely compromised the NOD2-driven expression of NICD, Jagged1, or COX-2 (Fig. 1, F and G, and supplemental Fig. S2, A–C)
We explored whether NOD2-mediated activation of PKC, ERK1/2, or p38 MAPK requires the involvement of iNOS/NO by utilizing peritoneal macrophages derived from wild type (WT) and iNOSϪ/Ϫ mice
Summary
Events regulating the activity of macrophages in terms of cytokine or chemokine production, receptor expression, and directed migration to secondary lymphoid organs for subsequent antigen presentation [2]. These attributes often have a major influence in determining the overall strength of the immune response. Signaling perturbations or genetic approaches implicated a critical role of cross-talk among members of Notch1-phosphoinositide 3-kinase (PI3K) in NOD2-mediated anti-inflammatory immune responses, including the expression of cyclooxygenase-2 (COX-2) and IL-10, in macrophages. Correlative evidence demonstrates that this mechanism operates in vivo as MDP, a known NOD2 agonist, triggered the expression of activated Notch, Jagged, or its target gene COX-2 in brain or splenocytes of mice. The current investigation identifies a novel role for Notch signaling in orchestrating functional attributes of NOD2 activation in an immunological milieu as well as in modulation of a distinct set of innate immunological parameters including COX-2 in innate immune cells
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