rel="nofollow" href="#ulink_cd7efda9-a284-5f1e-9276-56bbd289da2c">6], making older adults a uniquely challenging patient population. Here, we will focus on the impact of inflammation on dysregulation of innate immune responses and relevant tissue microenvironments that influence immune cellular function.
Critical Functions of Innate Immunity
The innate immune system is responsible for initial control of pathogens by directly eliminating infections, engaging nearby cells, and recruiting adaptive immune cells. In contrast to the adaptive immune system, which requires training and is exquisitely specific to particular pathogens, the innate immune system senses and responds to numerous infections directly. The innate immune system is composed of multiple cell types with distinct critical functions both in the circulation and following infiltration into tissues to provide early responses to infection or injury. Innate immune cells such as neutrophils and monocytes circulate throughout the body and are capable of rapidly infiltrating tissues; macrophages and dendritic cells (DCs) reside within tissue and have important roles in tissue surveillance and antigen presentation. Innate immune cells rely on a variety of pattern recognition receptors (PRRs) to sense tissue disturbance and also recognize pathogenic invasion. Membrane-associated Toll-like receptors (TLRs) on the cell surface and within endosomes sense diverse structural patterns associated with pathogens such as lipoproteins, lipopolysaccharide, flagellin, and nucleic acids. Numerous studies have reported diminished responsiveness to TLR ligands in innate immune cells from elderly donors as compared to younger donors and are discussed in more detail in the sections below. Nod-like receptors and retinoic acid-inducible gene-I (RIG-I)-like receptors are cytosolic sensors that respond to bacterial or viral molecular components to initiate inflammatory responses that limit pathogen spread. While aging affects each of these cell types and functional responses differently, some unifying mechanistic alterations offer insights to immune dysfunction in aging.
Neutrophils
Peripheral blood polymorphonuclear leukocytes (PMNs), the most abundant circulating white blood cells, account for 45–75% of circulating leukocytes. An estimated 1011 PMNs are released from the bone marrow daily to maintain a continuous supply of these crucial yet short-lived terminally differentiated cells. PMNs circulate throughout the body and therefore can potentially impact every tissue. They are rapid early responders to sites of infection or tissue injury and have high phagocytic and inflammatory capacity to limit pathogen spread. PMNs also contribute to chronic sterile inflammatory diseases such as gout in which they periodically accumulate and reactivate in afflicted joints causing debilitating pain in patients [7].
Despite their abundance and high inflammatory capacity, PMNs are less well characterized in the field of aging immunology. PMNs from older donors have lower TLR1 expression that correlates with reduced activation of TLR1-dependent IL-8, CD11b, and glucose uptake [8]. While PMNs from healthy elderly donors have reduced phagocytic (FITC-labeled E. coli) capacity and increased superoxide in response to fMLP and PMA [9, 10], generalization of these findings has been complicated by differences noted from different stimuli and experimental conditions [11]. PMNs from elderly individuals also show reduced actin polymerization [12, 13], suggesting impairments in chemotaxis. Indeed, in support of this possibility, PMNs isolated from aged mouse bone marrow exhibited reduced chemotaxis [14]. In the aged, poor chemotaxis is proposed to prolong PMN presence in tissue, causing collateral tissue damage [14, 15].
PMNs can undergo a novel form of cell death, NETosis, in which DNA content containing digestive and inflammatory enzymes is extruded from the cell. NETosis is a unique method to control pathogenic spread but is also recently implicated in sterile inflammation [16–18]. PMNs from old mice have impaired ability to undergo NETosis in response to in vivo cecal ligation and puncture-induced model of sepsis and also in vitro after stimulation with TLR2 ligands, suggesting a cell-intrinsic defect in signaling to induce NET formation and/or extrusion [19, 20]. In parallel with these impairments, however, human PMNs from healthy older donors maintain their ability to activate the NLRP3 inflammasome when stimulated in vitro [21]. Despite certain PMN functions being retained during aging, the accumulated defects that have been identified outnumber them, and these multiple defects in critical early responding cells allow more rapid pathogenic spread early after infection, putting the elderly host at increased susceptibility to infection and morbidity.
Monocytes
Monocytes are a heterogeneous subset of circulating myeloid cells that can infiltrate tissues and differentiate into macrophages or DCs. Their normal functions include phagocytosis, antigen presentation, and cytokine production. Multiple subsets of monocytes can be found in human blood at different stages of differentiation and maturity that are distinguishable by CD14 and CD16 expression [22]. Monocytes from older subjects have reduced production of cytokines after TLR1/2 stimulation that was associated with reduced surface TLR1 expression [23]; a generalized alteration in TLR-induced CD80 and CD86 expression correlates with reduced responses to influenza vaccination [24]. Monocytes from older subjects also have significantly diminished IFN-α/β responses to RIG-I stimulation [25]. Interestingly, these same monocytes retain the ability to produce proinflammatory cytokines upon stimulation, suggesting that aging may lead to cell-intrinsic dysregulation specifically in the IFN arm of this response [25, 26]. As there is no evidence of altered basal IFN expression with age, impaired IFN induction is representative of a model of age-related reduced dynamic range distinct from that of TLR-mediated proinflammatory cytokine induction. However, a significantly higher percentage of unstimulated monocytes from older donors exhibited nuclear NF-κB (p65) translocation, i.e. a higher activation status at baseline, and these cells secreted significantly more TLR5-induced IL-8 compared to monocytes from younger individuals [27], representing a possible avenue for vaccine adjuvant design. The age-related defects in monocytes have not yet been reported in other innate immune cells and highlight that each cell subset accumulates its own functional defects ultimately culminating in impaired innate immune protection during aging.
Macrophages
Macrophages are versatile innate immune cells that are important for initiating proinflammatory immune responses in addition to roles in phagocytosis, resolution, and tissue repair after injury. In the steady-state, anti-inflammatory macrophages help maintain homeostatic conditions within the tissue and become activated in response to infection or injury. Activated macrophages can secrete a variety of cytokines (e.g., TNFα, IL-1β, NO) that prime the inflammatory immune response and chemokines (MIP-2, KC) that recruit additional immune