**3.3 RAGE and neutrophils**

Neutrophils are phagocytic leukocytes of innate immune system circulating in the blood in a dormant state. Their activation is initiated in the early stages of inflammation and mechanisms for pathogen clearance include release of cytotoxic granules, cytokines, and reactive oxygen species (ROS). Neutrophils possess a unique ability to form neutrophil extracellular traps (NET) when undergoing altered cell death which have unique antimicrobial properties. Moreover, neutrophils can engage with and modulate activity of other immune cells such as T and B lymphocytes, NK cells and DCs. This can lead to exacerbation of autoimmune disorders such as systemic lupus erythematosus (SLE), multiple sclerosis and autoimmune diabetes [56–58].

*The Role of the Receptor for Advanced Glycation Endproducts (RAGE) in Type 1 Diabetes… DOI: http://dx.doi.org/10.5772/intechopen.108528*

In NOD mice activated neutrophils are recruited to the pancreatic islets initiating development of autoimmune diabetes and facilitating recruitment of CD8<sup>+</sup> T cells and DCs. Studies in NOD mice shown that migration of neutrophils plays pivotal role in disease progression and preventing it halts or reverses disease development [56, 59]. Similarly, neutrophil infiltrates were found in human pancreata prior to T1DM onset and in individuals with overt disease where there was an evidence of NET formation highlighting pathogenicity of the infiltrating neutrophils. Furthermore, neutrophils from the peripheral blood of autoantibody negative at-risk individuals, displayed a unique molecular signature with overexpression of interferon-related genes [60]. These data reinforce the importance of neutrophils in the initiation and progression of T1DM.

It was previously demonstrated that RAGE expression on human neutrophils and binding to AGEs was associated with impaired neutrophil function, in particular bacterial killing [61]. In the murine streptozotocin induced T1DM model the RAGE ligand S100 calcium-binding proteins A8/A9 (S100A8/A9) are released by neutrophils binding to RAGE on hepatic Kupffer cells leading to increase of IL-6 thrombopoietin production associated with atheroprogression in humans [62]. Albeit limited, these data support the importance of RAGE axis in effector immune populations which may be important for the development of T1DM.
