Innate immunity in aging: impact on macrophage function

Innate and adaptive immune functions decline with age, leading to increased susceptibility to infectious diseases and cancer, and reduced responses to preventive vaccination in the elderly population. Macrophages function as 'pathogen sensors' and play an important role in the initiation of inflammatory responses, elimination of pathogens, manipulation of the adaptive immune response and reparation of damaged tissue. In this paper, we review the literature addressing the impact of aging on the macrophage population.     

Innate immunity and adjuvants

Innate immunity was for a long time considered to be non-specific because the major function of this system is to digest pathogens and present antigens to the cells involved in acquired immunity. However, recent studies have shown that innate immunity is not non-specific, but is instead sufficiently specific to discriminate self from pathogens through evolutionarily conserved receptors, designated Toll-like receptors (TLRs). Indeed, innate immunity has a crucial role in early host defence against invading pathogens. Furthermore, TLRs were found to act as adjuvant receptors that create a bridge between innate and adaptive immunity, and to have important roles in the induction of adaptive immunity. This paradigm shift is now changing our thinking on the pathogenesis and treatment of infectious, immune and allergic diseases, as well as cancers. Besides TLRs, recent findings have revealed the presence of a cytosolic detector system for invading pathogens. I will review the mechanisms of pathogen recognition by TLRs and cytoplasmic receptors, and then discuss the roles of these receptors in the development of adaptive immunity in response to viral infection.     

Innate immunity: involvement of new neuropeptides

Secretory granules of chromaffin cells from the adrenal medulla store catecholamines and a variety of peptides that are secreted in the extracellular medium during exocytosis. Among these fragments, several natural peptides displaying antimicrobial activities at the micromolar range have been isolated and characterized. We have shown that these peptides, derived from the natural processing of chromogranins (CGs), proenkephalin-A (PEA) and free ubiquitin (Ub), are released into the circulation and display antibacterial and antifungal activities. In this review we focus on three naturally secreted antimicrobial peptides corresponding to CGA1–76 (vasostatin-I), the bisphosphorylated form of PEA209–237 (enkelytin) and Ub. In addition, the antimicrobial properties of the synthetic active domains of vasostatin-I (CGA47–66 or chromofungin) and Ub (Ub65–76 or ubifungin) are reported.     

Innate immunity and biodefence vaccines

Host defence in vertebrates is achieved by the integration of two distinct arms of the immune system: the innate and adaptive responses. The innate response acts early after infection (within minutes), detecting and responding to broad cues from invading pathogens. The adaptive response takes time (days to weeks) to become effective, but provides the fine antigenic specificity required for complete elimination of the pathogen and the generation of immunologic memory. Antigen-independent recognition of pathogens by the innate immune system leads to the rapid mobilization of immune effector and regulatory mechanisms that provide the host with three critical advantages: (i) initiating the immune response (both innate and adaptive) and providing the inflammatory and co-stimulatory context for antigen recognition; (ii) mounting a first line of defence, thereby holding the pathogen in check during the maturation of the adaptive response; and (iii) steering the adaptive immune system towards the cellular or humoral responses most effective against the particular infectious agent. The quest for safer and more effective vaccines and immune-based therapies has taken on a sudden urgency with the increased threat of bioterrorism. Only a handful of vaccines covering a small proportion of potential biowarfare agents are available for human use (e.g. anthrax and small pox) and these suffer from poor safety profiles. Therefore, next generation biodefence-related vaccines and therapies with improved safety and the capacity to induce more rapid, more potent and broader protection are needed. To this end, strategies to target both the innate and adaptive immune systems will be required.     

Innate immunity against viruses

Viruses are obligate parasites which are able to infect cells of all living organisms. Multiple antiviral defense mechanisms have appeared early in evolution of the immune system. Higher vertebrates have the most complex antiviral immunity which is based on both innate and adoptive immune responses. However, majority of living organisms, including plants and invertebrates, rely exclusively on innate immune mechanisms for protection against viral infections. There are some striking similarities in several components of the innate immune recognition between mammals, plants and insects, rendering these signaling cascades as highly conserved in the evolution of the immune system. This review summarizes recent advances in the field of innate immune recognition of viruses, with particular interest on pattern-recognition receptors.     

Innate immunity in tuberculosis: myths and truth

Tuberculosis is the most important bacterial infection world wide. The causative agent, Mycobacterium tuberculosis survives and proliferates within macrophages. Immune mediators such as interferon gamma (IFN-gamma) and tumour necrosis factor alpha (TNF-alpha) activate macrophages and promote bacterial killing. IFN-gamma is predominantly secreted by innate cells (mainly natural killer (NK) cells) and by T cells upon instruction by interleukin 12 (IL-12) and IL-18. These cytokines are primarily produced by dendritic cells and macrophages in response to Toll-like receptor (TLR) signalling interaction with tubercle bacilli. These signals also induce pro-inflammatory cytokines (including IL-1beta and TNF-alpha), chemokines and defensins. The inflammatory environment further recruits innate effector cells such as macrophages, polymorphonuclear neutrophils (PMN) and NK cells to the infectious foci. This eventually leads to the downstream establishment of acquired T cell immunity which appears to be protective in more than 90% of infected individuals. Robust innate immune activation is considered an essential prerequisite for protective immunity and vaccine efficacy. However, data published so far provide a muddled view of the functional importance of innate immunity in tuberculosis. Here we critically discuss certain aspects of innate immunity, namely PMN, TLRs and NK cells, as characterised in tuberculosis to date, and their contribution to protection and pathology.     

Innate immunity: unfolding the neuro-immuno connections

The innate immune system maintains health and fitness during infection by eliminating infectious agents and by limiting damage caused by pathogens or immune activation. The nervous system contributes to innate immunity by modulating the expression of antimicrobial peptides and by regulating the unfolded protein response.     

Innate immunity: the worm fights back

Innate immunity is an evolutionarily ancient defense system that enables animals and plants to resist invading microorganisms. Recent studies have demonstrated the existence of innate immune responses in Caenorhabditis elegans.     

Innate immunity: cutaneous expression of Toll-like receptors

Toll receptors were first identified as an essential molecule for embryonic patterning in Drosophila and were subsequently shown to be a key in antibacterial and antifungal immunity in adult flies. Toll receptors have been conserved throughout evolution. In mammals, TLRs have been implicated in both inflammatory responses and innate host defense to pathogens. The 11 different TLRs recognize conserved molecular patterns of microbial pathogens termed pathogen-specific molecular patterns (PAMPs), that permit to confer responsiveness to a wide variety of pathogens. Endogenous ligands are also able to activate TLRs. All adult tissue is capable to express at least one of member of TLR family, but a largest repertoire of TLRs is found in tissues exposed to the external environment. The TLR activation induce the NF-kappaB translocation to the nucleus and cytokine secretion. Since the primary function of skin is to provide an effective barrier against outside agression, it is likely that keratinocytes may play a role in a rapid and efficient host defence system, and the fact that keratinocytes are capable of expressing a wide variety of TLRs is subsequently not surprising.