CNS & Neurological Disorders - Drug Targets, 2011, 10, 25-43 25 1871-5273/11 $58.00+.00 © 2011 Bentham Science Publishers Activation and Control of CNS Innate Immune Responses in Health and Diseases: A Balancing Act Finely Tuned by Neuroimmune Regulators (NIReg) Jean-Jacques Hoarau 1 , Pascale Krejbich-Trotot 1 , Marie-Christine Jaffar-Bandjee 1,2 , Trina Das 1 , Gerard-Vincent Thon-Hon 1 , Shiril Kumar 1 , Jim W. Neal 3 and Philippe Gasque *,1 1 GRI, Immunopathology and Infectious Disease Research Grouping (IRG, GRI), University of La Reunion, Reunion Island 2 Virology Laboratory, CHR Felix Guyon, St Denis, Reunion Island 3 Neuropathology Laboratory, Cardiff Medical School, UK Abstract: Innate immunity is an arsenal of molecules and receptors expressed by professional phagocytes, glial cells and neurons and involved in host defence and clearance of toxic and dangerous cell debris. However, any uncontrolled innate immune responses within the central nervous system (CNS) are widely recognized as playing a major role in the development of autoimmune disorders and neurodegeneration, with multiple sclerosis (MS) and Alzheimer’s diseases (AD) being primary examples. Critically, neuroimmune regulatory proteins (NIReg) may control the adverse immune responses in health and diseases. NIRegs are found mainly on neurons, glia, endothelia and ependymal cells and include GPI-anchored molecules (CD24, CD90, complement regulators CD55 and CD59), molecules of the immunoglobulin superfamily (siglec CD22, Siglec 10, CD200, ICAM-5) and others (CD47, fractalkine, TAM receptor tyrosine kinase and complement C3a and factor H). These regulators modulate the innate immune response in the CNS and for instance critically control the level of phagocytosis and inflammation engaged by resident microglia and infiltrating immune cells. Others will sequester and neutralize proinflammatory molecules such as HMGB1 and DNA. Moreover, some NIRegs can instigate the recruitment of stem cells to mediate tissue repair. In the absence of these regulators, when neurons die by apoptosis, become infected or damaged, microglia and infiltrating immune cells are free to cause injury and an adverse inflammatory response in acute and chronic settings. The therapeutic applications of NIRegs should be exploited given their natural and selective healing properties. Keywords: Innate immunity, CNS, pathogen, apoptotic, necrotic, DAMP, SAMP, NIReg. 1. INTRODUCTION: DRIVING A PROTECTIVE AND SELF- CONTROLLED INNATE IMMUNE RESPONSE IN THE CNS, A BALANCING ACT BETWEEN ACTIVATORS AND INHI- BITORS The essence of the innate immune system is to clear harmful pathogenic substances (called herein ‘danger’) in the shape of a microbe (virus, bacteria, fungi, and parasite), apoptotic debris or toxic proteins such as prions or amyloid fibrils [1, 2]. Failure to mount this protective response could lead to chronic infectious diseases, autoimmunity or chronic neurodegeneration [3]. Tissue repair mechanisms will ensue with the complete removal of toxic substances together with the recruitment of stem cells to replenish the dead cells. While professional innate immune cells such as macrophages, natural killer and dendritic cells are the canonical soldiers of host defence, the so-called ‘amateur’ neighbouring cells such as glial cells, ependymal cells, neurons, endothelial cells, and fibroblasts also contribute to innate immunity in the CNS [2]. This paradigm is particularly important on the grounds that a controlled immune response is vital to protect the CNS from viral encephalitis, multiple sclerosis and Alzheimer’s disease. First and foremost, a robust innate immune response must be engaged against the microbial intruders and toxic substances and is based on the recognition of ‘non-self pathogens’ and ‘altered-self’ dangerous patterns, by molecules and receptors expressed essentially by microglia but also found on astrocytes, ependymal cells, endothelial cells and neurons [4]. These molecules and *Address correspondence to this author at the Immunopathology and Infectious disease Research Grouping (IRG, GRI), CYROI Biomedical Research Building, 2 rue M Riviere, 97400, St Denis, Reunion Island; Tel: 00 262 692 597037; 00 262 262 938836; Fax: 00 262 262 938801; E-mails: gasque@univ-reunion.fr, gasquep@hotmail.com receptors are called pattern recognition receptors (PRRs) which can be either cytoplasmic, released in soluble forms, displayed on the cell membrane or contained in endosomes [5]. These receptors act rarely alone, but in concert to bind and transduce cellular signals derived from pathogenic molecules called pathogen-associated molecular patterns (PAMPs) or from damage/danger-associated molecular patterns (DAMPs) [6]. The outcome of these interactions is dependent on the nature of the ligands, and upon the nature and combination of the ligated receptors. In principle, recognition of pathogens and other danger signals from necrotic cells will lead to a robust proinflammatory response. Whereas much attention has been focused on the properties and activities of the Toll-like receptors (TLRs) in this process, many other CNS innate immune molecules have been described (e.g. nucleic acid and bacterial peptidoglycan sensors, complement, C-type lectins, CD91, receptor for advanced glycation endproducts (RAGE) and other scavenger receptors) [7, 8]. The decoding and sampling of the microenvironment for danger signals will contribute to a local humoral and adaptive T and B cellular response to drive the removal of the harmful intruders. The amplitude and duration of the immune response should in principle be self limiting, because the molecular patterns that trigger and sustain the innate response are cleared and the effector T cells and B cells undergo programmed cell death. Hypothalamus, pituitary, adrenal (HPA) axis activation during inflammation also elevates glucocorticoid synthesis, which further attenuates proinflammatory signaling [9]. The inflammatory responses that establish feed-forward loops may overwhelm normal resolution mechanisms. Although some innate immune molecules induce beneficial effects (e.g., phagocytosis of debris and apoptotic cells by complement), and tissue repair processes through the recruitment of stem cells from the distant niches, uncontrolled inflammation may result in production of neurotoxic factors that amplify underlying disease states (Table 1).