The role of nucleotide-binding oligomerization domain 1 during cytokine production by macrophages in response to Mycobacterium tuberculosis infection

Abstract

Tuberculosisdue toMycobacteriumtuberculosisinfectionis a leading cause of death worldwide. Recognition of this pathogen is crucial for the activation of innate and adaptive immune responses.Nucleotide-bindingoligomerizationdomain(Nod)1and Nod2 are cytoplasmic receptors that can detect unique muropeptides of bacterial peptidoglycan. Nod2 is critical for the initiation of the host immuneresponseagainst M.tuberculosisinfection, however theroleof Nod1 remains largely unknown. We investigated theroleof Nod1 with respect tocytokineproductionby bone marrow-derivedmacrophages(BMDMs) inresponseto M.tuberculosisinfection.Productionof proinflammatory cytokines, such as IL-6, TNF-α, and IL-1β were induced in BMDMs;cytokinelevels were not affected by a deficiency in Nod1. Activation of NF-κB and MAPKs was also comparable between wild-type and Nod1-deficient BMDMs. Levels of IL-6 and IL-1β were reduced in Nod1/Nod2 double-deficient BMDMs to a greater extent than in Nod2-deficient cells. Furthermore, when signaling of Toll-like receptors (TLRs) was inhibited by lipopolysaccharide pre-treatment,cytokineproductionwas diminished in Nod1-deficient BMDMs. Our results indicate that Nod1 cooperates with Nod2 or TLRs to produce cytokines inmacrophagesinresponseto M.tuberculosisinfection.