Increased IRAK-M in peritoneal macrophages of NOD mice suggests in vivo exposure to bacterial endotoxins from the gut (INC6P.343)

Macrophages play an important role in innate immune reactions, and peritoneal macrophages guard the sterility of this compartment mainly against microbial threat from the gut. Type-1 Diabetes (T1D) is an autoimmune disease in which gut microbiota and gut immune system appear to play a role. We have observed increased permeability and free radical production of gut epithelium in nonobese diabetic (NOD) mice. Impaired barrier function could lead to bacterial endotoxin leakage to peritoneal cavity. To seek for extraintestinal consequences of impaired barrier function, we characterized peritoneal lavage cells from young NOD mice after weaning. We detected a rapid increase in the number of macrophages in 1-2 weeks from weaning in NOD mice compared to C57BL/6 and BALB/c mice, and to NOD mice fed an antidiabetogenic diet (ProSobee), which improves gut barrier function. Upon LPS stimulation ex vivo, macrophages produced low amounts of TNF-α and showed reduced expression of CD40. Expression of TLR signalling pathway negative regulator, Interleukin-1 Associated Kinase -M (IRAK-M) was increased, indicating prior in vivo exposure to TLR-4 ligand(s). Upon further phenotyping, increased levels of ARG1 were observed suggesting in vivo differentiation towards M2-like phenotype. Bacterial endotoxins in peritoneal cavity may contribute to autoreactive T-cell activation by increased production of cytokines and activation of antigen-presenting cells in pancreatic lymph nodes.