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Influenza viral infections often lead to increased mortality in older people. However, the mechanisms by which aging impacts immunity to influenza lung infection remain unclear. We employed a murine model of influenza infection to identify these mechanisms. With aging, we found reduced numbers of alveolar macrophages, cells essential for lung homeostasis. We also determined that these macrophages are critical for influenza-induced mortality with aging. Furthermore, aging vastly alters the transcriptional profile and specifically down-regulates cell cycling pathways in alveolar macrophages. Aging impairs the ability of alveolar macrophages to limit lung damage during influenza infection. Moreover, aging decreases alveolar macrophage phagocytosis of apoptotic neutrophils, downregulates the scavenging receptor CD204, and induces retention of neutrophils during influenza infection. Thus, aging induces defective phagocytosis by alveolar macrophages and increases lung damage. These findings indicate that therapies that enhance the function of alveolar macrophages may improve outcomes in older people infected with respiratory viruses.

The aim of candidate universal influenza vaccines is to provide broad protection against influenza A and B viruses. Studies have demonstrated that broadly reactive antibodies require Fc–Fc gamma receptor interactions for optimal protection; however, the innate effector cells responsible for mediating this protection remain largely unknown. Here, we examine the roles of alveolar macrophages, natural killer cells, and neutrophils in antibody-mediated protection. We demonstrate that alveolar macrophages play a dominant role in conferring protection provided by both broadly neutralizing and non-neutralizing antibodies in mice. Our data also reveal the potential mechanisms by which alveolar macrophages mediate protection in vivo, namely antibody-induced inflammation and antibody-dependent cellular phagocytosis. This study highlights the importance of innate effector cells in establishing a broad-spectrum antiviral state, as well as providing a better understanding of how multiple arms of the immune system cooperate to achieve an optimal antiviral response following influenza virus infection or immunization.

Older people exhibit increased mortality to infections and cancer as compared to younger people, indicating that aging impairs immunity. Dendritic cells (DCs) are key for bridging the innate and adaptive arms of the immune system by priming antigen specific T cells. Discerning how aging impacts DC function to initiate adaptive immune responses is of great biomedical importance as this could lead to the development of novel therapeutics to enhance immunity with aging. This review details reports indicating that aging impairs the antigen presenting function of DCs but highlights other studies indicating preserved DC function with aging. How aging impacts antigen presentation by DCs is complex and without a clear unifying biological underpinning.

The murine Mac-2 protein is a galactose-and IgE-binding lectin secreted by inflammatory macrophages. We describe here the cloning and characterization of a cDNA representing the human homolog of Mac-2 (hMac-2). The amino acid sequence derived from the hMac-2 cDNA indicates that the protein is evolutionarily highly conserved, with 85% of its amino acid residues being similar to those in the murine homolog. This conservation is especially marked in the carboxyl-terminal lectin domain. The amino-terminal half of the protein is less conserved but still contains the repetitive prolineglycine-rich motif seen in the mouse protein. hMac-2 synthesized in vitro is recognized by the M3/38 monoclonal antibody to Mac-2 and binds to the desialylated glycoprotein asialofetuin and to laminin, a major component of basement membranes.These findings are discussed in the context of the potential functions of hMac-2.Macrophages activated during the course of acute or chronic inflammation release a number of soluble proteins which mediate or regulate the effects of the inflammatory response. Understanding the function and mode of regulation of these monokines is critical to devising strategies for therapeutic intervention in inflammatory disorders. The murine Mac-2 antigen was originally described by Ho and Springer (1) and was shown to be expressed at a high level on the surface of inflammatory macrophages. We recently cloned cDNAs encoding Mac-2 and showed that the protein is secreted and has the characteristics of a galactose-specific lectin (2). A search ofthe computer data bases revealed that it had been identified independently by two other groups on the basis of its carbohydrate-binding property. Wang and colleagues (3,4) IgE (6). We have shown that Mac-2 also has the ability to bind murine IgE (2).Recently, yet another function has been revealed by the work of Woo et al. (7), who showed that Mac-2 is the major nonintegrin laminin-binding protein synthesized by murine inflammatory macrophages, indicating a potential role in macrophage-extracellular matrix interactions.Given the number of functions and subcellular locations proposed for Mac-2, further studies are clearly warranted. The high expression of this protein in inflammatory macrophages suggests that it has an important function in inflammation. In view of the potential involvement of this protein in processes relevant to human disease, we were interested in determining whether a human homolog of Mac-2 existed. In the present report we describe the cloning of the human homolog of Mac-2 (which we have designated hMac-2, for human Mac-2 antigen)* and show that the primary structure of the two proteins is highly conserved, especially in the lectin domain. The hMac-2 synthesized in vitro is recognized by the M3/38 monoclonal antibody to Mac-2 (1) and behaves like a galactose-specific lectin in its binding to the desialylated glycoprotein asialofetuin. It also binds to purified laminin, thus confirming and extending the results of Woo et al. (7). MATERIALS AND METH...