The concept of innate immunity is phylogenetically ancient and first appeared in multicellular organisms. Unlike the adaptive immune response, innate immune mechanisms do not rely on ‘memory’ and reset to baseline following clearance of encountered pathogens. The adaptive immune response is dependent on several aspects of innate immunity that result in the generation of antigen-specific lymphocytes and memory cells that are capable of rapidly responding to recurrent infections, thereby providing long-lasting immunity.

In order for a pathogen to successfully infect its host, several host defences, including physical barriers, must be breached. These innate barriers include epithelial surfaces and respiratory, reproductive tract and gastrointestinal mucosal surfaces. In the context of the central nervous system (CNS), the blood–brain barrier (BBB) and the blood–cerebrospinal fluid barrier (BCSFB) are considered the most important and relevant barriers; both can be breached during CNS injury. The BBB is both a physical and biochemical barrier, consisting of tight junctions within an endothelial cell barrier that restricts the diffusion of pathogens and large hydrophilic molecules that would otherwise disrupt homeostasis in the CNS. In addition to endothelial cells, astrocytes and pericytes are also integral in forming the BBB and maintaining its integrity by regulating blood flow and providing structural and metabolic support. The BCSFB is located at the tight junctions surrounding the epithelial cells on the surface of the choroid plexus, which secrete cerebrospinal fluid (CSF) and express specific transporter proteins that regulate the exchange of molecules between the blood and the CSF. If a given pathogen is successful and infects its host, an inflammatory response in the host is initiated. While the inflammatory process is very complex, in simple terms, it begins with an innate response whereby local vasodilation of vascularized tissue, including the CNS, leads to fluid and leukocyte accumulation. This increase in blood flow is manifested by symptoms such as swelling (oedema) and redness. Within the blood vessels, increased hydrostatic pressure can lead to the contraction of endothelium and the leakage of fluids, such as collectins (i.e. soluble lectin molecules and mannan-binding protein) and complement, which can bind to the surfaces of microbes in a process termed opsonization, facilitating their phagocytosis or direct lysis.

In order for immune cells to reach sites of infection or injury, various molecules and chemoattractants (e.g. bacterial products and chemokines) must promote the expression of adhesion molecules (selectins and integrins) on both immune cells and vascular endothelial cells, while chemokines and activated complement components (e.g. C5a) create a gradient that can lead to extravasation of peripheral blood cells into the infected or injured tissue. Upon reaching the site of injury, phagocytic cells (e.g. neutrophils and macrophages) must identify both opsonized and non-opsonized dying cells, pathogens and cellular debris. The phagocyte can then deliver antimicrobial molecules, engulf the elements and, if necessary, kill the microbe through production of reactive oxygen species (ROS). The detailed mechanisms by which innate immune cells recognize microbes and sites of tissue injury will be discussed in subsequent sections of this chapter.

All cells of the immune system, in addition to erythrocytes and platelets, are derived from pluripotent haematopoietic stem cells that develop in the bone marrow. From the bone marrow, leukocytes can either migrate to specialized tissues or reside within the circulatory and/or lymphatic systems. Haematopoietic stem cells can further give rise to both common lymphoid and myeloid progenitors. Cells within the lymphoid lineage differentiate into cells of the adaptive immune system (e.g. B and T lymphocytes) in addition to natural killer (NK) cells. NK cells are large granular cells that lack antigen-specific receptors, but can recognize and kill tumour and pathogen-infected cells in a major histocompatibility complex (MHC) unrestricted manner, and they are therefore considered part of the innate immune system. Common myeloid progenitor cells differentiate into cells of the innate immune system, including granulocytes, mast cells, dendritic cells (DCs) and monocytes and macrophages.

Granulocytes are also known as polymorphonuclear cells and can be divided into neutrophils, eosinophils and basophils. During infection and inflammation, these cells can migrate into tissues, where they are found in very large numbers but are relatively short-lived. As stated in this chapter, neutrophils are highly phagocytic and are capable of engulfing and degrading microbes by releasing ROS and hydrolytic enzymes. Of the cells comprising the innate immune system, neutrophils are the most numerous and can readily migrate to sites of injury through various chemotactic gradients. While the roles of eosinophils and basophils have been largely described in the context of allergy, eosinophils in particular have been shown to also possess antiparasitic activity (Rosenberg et al., 2012). In neuromyelitis optica (NMO), an inflammatory demyelinating disease of the CNS, active lesions have been characterized by infiltration of macrophages, perivascular granulocytes and eosinophils (Lucchinetti et al., 2002). Both intact and degranulated eosinophils were found within active lesions; however, their exact function is unknown, and it is unclear whether infiltration of eosinophils is a primary or secondary event in NMO. It has been suggested that complement activation in lesions may result in the production of chemotactic factors that recruit eosinophils into the CNS (Lucchinetti et al., 2002). In addition to their capacity to release ROS, cytokines and growth factors, eosinophils have also been shown to possess antiviral activities through the production of RNases.

Mast cells play significant roles in allergy and inflammation, and they are also important in their ability to protect the body from certain pathogens, including parasites (e.g. intestinal worms). While mast cells are capable of secreting a variety of different soluble factors, including histamine, proteases, proteoglycans (heparin), prostaglandins, thromboxanes and leukotrienes, these cells are believed to release several different cytokines that can impact innate immunity, including tumour necrosis factor alpha (TNFα), interleukin-1 (IL1), IL6 and interferon gamma (IFNγ) (Skaper et al., 2012). In the inflamed CNS, mast cells have been found in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) lesions (Brenner et al., 1994; Theoharides, 1990), and can directly cause demyelination and oligodendrocyte death (Johnson et al., 1988; Theoharides et al., 1993; Medic et al., 2010).

Much of the current chapter will focus on innate immune cells that are termed professional antigen-presenting cells and include DCs and macro-phages. The CNS resident macrophages, referred to as microglia, will also be discussed in detail. DCs are highly phagocytic cells that possess long extensions resembling the dendrites of neurons. A high density of DCs can be found in epithelial surfaces and in areas that encounter the external environment. Unlike other phagocytic immune cells, DCs specialize in antigen processing and presentation, and effectively present antigen to lymphocytes and initiate adaptive immune responses. Upon antigen uptake, DCs migrate to lymph nodes where they increase their expression of costimulatory molecules, present antigen via MHC proteins and can subsequently activate B cells, naïve T cells and antigen-specific memory T cells that will undergo clonal expansion. It is important to note that both macrophages and B cells can similarly activate T cells; however, the spatial distribution of DCs within the lymph nodes makes them superior antigen-presenting cells and the most potent activators of T cells.

In humans, there are two classes of DCs that possess distinct properties that can influence immune responses. These two major cell types are myeloid DCs (mDCs; also termed classical or conventional DCs) and plasmacytoid DCs (pDCs). mDCs are similar to monocytes and are the conventional dendritic cell responsible for activating naïve T cells. There are several different subsets of these specialized DCs; however, all cells express MHC and costimulatory molecules specialized for activating the adaptive immune response (Johnson et al., 2011). While pDCs are also capable of activating T and B cells, they have been documented to play a significant role in responding to viral infections and express specific Toll-like receptors (TLRs) that are able to sense viral infections (TLR7 and TLR9). In addition, pDCs secrete type I interferons (IFNα and IFNβ), which are specialized cytokines that can further activate the immune system and rid the body of viral infections.

Monocytes, as well as DCs, also arise from specialized myeloid progenitor cells found in the bone marrow. Monocytes circulate within the blood and are capable of extravasation into tissues to become macrophages. Also included in the myeloid cell category are specialized and tissue-specific macrophages, which have been suggested to arise from the yolk sac (Gomez Perdiguero et al., 2013). Depending on their location within the body, examples of tissue-specific macrophages include alveolar macrophages (lung), Kupffer cells (liver), osteoclasts (bone) and microglia (CNS). Previous fate-mapping studies have demonstrated that adult microglia are derived from haematopoietic progenitors in the extra-embryonic yolk sac between embryonic day 7.0 (E7.0) and E9.0 (Ginhoux et al., 2010). Like DCs, these additional myeloid cell types (e.g. monocytes, macrophages and organ-specific myeloid cells) are phagocytic, express MHC class II and costimulatory molecules and promote adaptive immune responses. However, monocytes and macrophages also secrete a wide array of cytokines and chemokines, which function to promote inflammation and recruit additional immune cells to sites of injury. In subsequent sections of this chapter, the phenotypes and specialized functions of these cells will be further discussed in the context of CNS infection, injury and repair.

Prior to activating the adaptive immune response, cells of the innate immune system first respond to pathogens, or danger signals, within their environment. DCs, macrophages and monocytes all possess both surface and intracellular receptors capable of recognizing pathogen-associated molecular patterns (PAMPs), which are small molecular patterns associated with specific classes of pathogens and microorganisms. These specialized patterns are recognized by different families of pattern recognition receptors (PRRs), and they include TLRs, nucleotide-binding oligodimerization domain (NOD)-like receptors (NLRs) and RIG-like receptors (RLGs). The concept of PRRs is important not only in the context of their specialized roles in mediating inflammation, but also in the pathology and identification of specialized and polarized cell types in diseased tissue, as discussed later in this chapter.

Within the CNS, inflammation and innate immunity are believed to contribute to the pathogenesis and neurodegeneration that occur in several diseases and conditions, including stroke, Alzheimer’s disease and demyelinating diseases such as MS. Traditional views that considered the CNS to be an ‘immune-privileged’ site are currently being challenged, whereby it is generally accepted that both innate and adaptive immune responses are important and highly relevant in the context of both CNS injury and repair. In the context of neuroinflammation, while there has been a plethora of research that has investigated the roles of innate immune cells (macrophages, DCs and granulocytes) in contributing to CNS disorders, more recent research has focussed on putative roles of CNS resident cells, including astrocytes and microglia. In the subsequent sections of this chapter, we will discuss the roles of the traditional innate immune cell populations in diseases of the CNS, as well as the emerging roles of CNS resident cells.