Summary
The innate immune response refers to the primitive, evolutionarily conserved, immune system that responds rapidly to a foreign stimulus. It has been long known to involve resident immune cells such as macrophages and dendritic cells (DC) and acts in consort with other “innate” protective mechanisms such as physical barriers (e.g. mucous), chemicals (e..g. free radicals), temperature controls, to form the body’s front-line defence systems. Not only does the innate immune response provide rapid defence, but also produces cytokines that amplify more innate responses, and importantly sculpts the ensuing adaptive immune response. These responses are mediated by cytokines and chemokines that are responsible for the development, recruitment and activation of infiltrating cells.
Thus, the innate immune response is the basis of the inflammatory response. The cardinal signs of rubor (redness), tumor (swelling), calor (heat), dolor (pain) and functio laesa (loss of function), are the result of increased blood flow, vascular permeability and cell infiltration caused by the cytokines and chemical products released from stimulated innate immune cells. These signs have been known for centuries and the cellular and cytokine details elaborated in recent decades. However, is only in the last 14 years that our appreciation of the innate immune system has been shaken from the now apparently naïve notion of an essentially non-specific response, to one with a degree of specificity and structure, albeit not as elaborate as the adaptive immune response. The discoverers of this response won the2011 Nobel Prize for this seminal contribution.
This revolution in our understanding of the innate immune system began with the discovery of the Drosophila Toll mutant as a developmental anomaly and subsequent demonstration of the role of the Toll receptor in protection from infection [1]. This was quickly followed by noting homology of the Toll gene with the interleukin-1 (IL1) cytokine family implicating a role in immune response [2], identification of mammalian homologues, designated Toll-like Receptors (TLRs) and demonstration of TLR4 as mediating the sensing and response to the prototypical inflammatory stimulus, lipopolysaccharide (LPS) [3]. Since these discoveries were occurring at a time of enormous technological advances such as high throughput DNA and RNA sequencing, high density microarrays and generation of gene targeted mice for in vivo validation of function, there was an explosion of discovery in the ensuing years [4]. These led to the identification of a family of up to 13 TLRs in mammals and the rapid identification of the signal transduction components such as the adaptor molecules, kinases, transcription factors and sets of genes involved in the innate response (Fig.1). The families of receptors that initiate innate immune responses to pathogens grew as it was realised that the TLRs could not explain responses to all pathogens. These included RIG-I-Like Helicases (RLHs), DNA sensors [4], Nod-Like Receptors (NLRs) [5] and C –type Lectins [6]. The expanded family of receptors which co-evolved with pathogenic microorganisms are commonly known as Pathogen Recognition Receptors (PRRs). Accordingly, the molecules that trigger these receptors are known as Pathogen Associated Molecular Patterns (PAMPs) [7, 8]. PAMPs are present in almost all invasive organisms, from bacteria to viruses and fungi, and are derived from the major families of molecules found in these organisms, including cell surface glycolipids,, nucleic acids, lipids, proteins and chemicals (Fig.1). The innate receptors or PRRs also recognise endogenous non-pathogen ligands such as extracellular matrix components, nucleic acids from dying or damaged cells, immune complexes, misfolded proteins and crystalline aggregates (e.g. uric acid, amyloid protein and cholesterol) which are referred to as Danger Associated Molecular Patterns (DAMPs) [9, 10].
The elaboration of components of the innate immune response has enabled a broader appreciation and definition of the innate immune system (Fig.1). While first thought to involve mainly resident immune cells such as macrophages and dendritic cells (DC), we now recognise it to also involve epithelial and other parenchymal cells that may form the first point of contact with the pathogen or stimulus. Our understanding of the innate signaling pathways that are upstream regulators of the cytokines that mediate immunity and inflammation, has opened the door to understanding the basis of diseases of the immune system, inflammatory diseases and cancers. Genes encoding innate immune signaling components are subjects of mutations in disease as well as targets for suppressive mechanisms evolved by pathogens to evade the host defences. The molecules within the innate pathways can be used as biomarkers of an immune response, genetic stratification for immune competence or disease susceptibility and as targets for therapeutics. Knowing and refining ligands to activate these pathways has informed vaccine and drug development efforts. Harnessing and expanding our knowledge of innate immune pathways and outcomes across species will be a crucial part of improved health in human, veterinary and agricultural endeavours [11].
