These can be divided into four main groups: acute injuries (mechanical traumas, ischemic stroke, etc.), neurodegenerative chronic diseases (Alzheimer’s disease, multiple sclerosis, etc.), brain
tumors (glioblastomas), and infections (HIV, drug discovery E. coli, etc.). While there is a lot to discuss regarding the role of innate immunity in infection, stroke, and brain tumors, we will focus this part of the discussion on the implication of the innate immune system in two chronic diseases: Alzheimer’s disease and multiple sclerosis. We will use these complex pathological states to highlight the integration of all cell types of the NVU and how they can be used efficiently to develop new comprehensive ways of targeting such diseases. Alzheimer’s disease is caused mainly
by the deposition of Aβ into plaques in the CNS. The innate immune system plays a role in the development Doxorubicin of the pathology as chronic exposure of microglia to Aβ leads to uncontrolled inflammation, the release of toxic free radicals, and reactive oxygen species, as originally described in postmortem studies (Uchihara et al., 1997; Cagnin et al., 2001). Furthermore, large scale genome-wide association studies (GWAS) of thousands of AD subjects have shown that among the ten genetic polymorphisms most tightly linked to the development of late onset AD, nine play a dominant role in immunological processes (Moraes et al., 2012). In the serum, cerebrospinal
fluid, and the cortex of affected patients, higher levels of IL-1β, IL-6, TNFα, IL-8, and TGFβ have all been reported (for in-depth Reviews, see Rubio-Perez and Morillas-Ruiz, 2012 and Akiyama et al., 2000). Similarly, both TLR2 and TLR4 are overexpressed in peripheral blood mononuclear cells from patients with AD (Zhang et al., 2012). It also appears that the main monocytic chemoattractant CCR2 and its ligand CCL2 are involved in the progression of AD (Naert and Rivest, 2011; Conductier et al., 2010; Westin et al., 2012). Furthermore, Suplatast tosilate while no genetic association at the TLR4 locus was found in GWAS for AD (Moraes et al., 2012), polymorphisms in the TLR4 gene were shown to increase the incidence of late-onset AD in populations from Italy (Balistreri et al., 2008; Minoretti et al., 2006) and China (Wang et al., 2011; Yu et al., 2012; Chen et al., 2012). The reported data on humans state that, in essence, AD is first and foremost an immunological disease. The main genetic risk factor identified in GWAS for late-onset AD is ApoE4 (Bettens et al., 2013). The family of Apolipoprotein E (ApoE) plays a major role in the transport of cholesterol and other lipids, mainly by the binding of LDLRs and LRPs (Mahley, 1988; Holtzman et al., 2012). Humans have three common alleles of apoE gene, apoEε2, apoEε3, and apoEε4, which give rise to three protein isoforms, ApoE2, ApoE3, and ApoE4 (Bell et al., 2012).