Advanced age is associated with defects in all of the cells of the innate immune system, including numbers, function, and early stages of activation. This review, presents the current state of the field on the impact of age on the innate immune system. The analysis of the literature suggests that a dysfunctional innate immune system is a contributing factor to aberrant outcomes after injury or infection and to the development of many of the diseases observed in the elderly. Gaining an understanding of the nature of the defects in innate immune cells may allow the development of therapeutic strategies aimed to restore innate immune function in aged individuals.

The hyperreactive systemic inflammatory response seen in aged individuals after lipopolysaccharide administration is accompanied by an exacerbated pulmonary inflammatory response, which may contribute to the higher mortality seen in the aged given an inflammatory insult.

Burn patients over the age of 60 are at a greater risk for developing pulmonary complications than younger patients. The mechanisms for this, however, have yet to be elucidated. The objective of this study was to determine whether increased chemoattraction plays a role in the age-related differences in pulmonary inflammation after burn injury. At 6 or 24 h after receiving sham or 15% total body surface area scald injury, lungs from young and aged mice were analyzed for leukocyte content by histological examination and immunostaining. Lungs were then homogenized, and levels of neutrophil chemokines, MIP-2 and KC, were measured. At 6 h after burn, the number of neutrophils was four times higher in the lungs of both burn groups compared with aged-matched controls (P<0.05), but no age difference was evident. At 24 h, in contrast, neutrophils returned to sham levels in the lungs of young, burn-injured mice (P<0.05) but did not change in the lungs of aged, burn-injured mice. Pulmonary levels of the neutrophil chemokine KC but not MIP-2 were consistently three times higher in aged, burn-injured mice compared with young, burn-injured mice at both time-points analyzed. Administration with anti-CXCR2 antibody completely abrogated the excessive pulmonary neutrophil content by 24 h (P<0.05), while not affecting the inflammatory response of the wounds. These studies show that CXCR2-mediated chemoattraction is involved in the pulmonary inflammatory response after burn and suggest that aged individuals sustaining a burn injury may benefit from treatment strategies that target neutrophil chemokines.

Here, we studied in vitro cytokine production by splenic macrophages obtained from young and aged BALB/c wild type (WT) and IL-6 knockout (IL-6 KO) mice. Relative to macrophages obtained from young WT mice given lipopolysaccharide (LPS), those from aged WT mice had decreased production of proinflammatory cytokines. In contrast, when compared to macrophages from young IL-6 KO mice, LPS stimulation yielded higher levels of these cytokines by cells from aged IL-6 KO mice. Aging or IL-6 deficiency did not affected the percentage of F4/80+ macrophages, or the surface expression of Toll-like receptor 4 (TLR4) and components of the IL-6 receptor. Overall, our results indicate that IL-6 plays a role in regulating the age-related defects in macrophages through alteration of proinflammatory cytokines, adding to the complexity of IL-6-mediated impairment of immune cell function with increasing age.

As we age, it is common for certain phenotypic changes to arise within the population. A number of observations have led scientists to believe that these changes result from an accumulation of cellular defects over time. With enough cell damage, tissue function is compromised and the risk for disease escalates. More importantly, when these defects arise in cells of the innate immune system, the body can no longer defend itself against a variety of pathologies. The main culprit for cellular damage seen with age is thought to be reactive oxygen and nitrogen species produced from endogenous metabolic pathways. To determine how an individual will age, it is thus important to consider all of the factors involved in both the production of and the response to oxidative stress. These factors include genetics, lifestyle, environment, and gender. Understanding the mechanisms of aging can allow us to develop strategies for overcoming the negative aspects of this process and ultimately to help individuals age more gracefully.

Critically ill patients that survive sepsis can develop a Persistent Inflammation, Immunosuppression, and Catabolism Syndrome (PICS), which often leads to extended recovery periods and multiple complications. Here, we utilized a cecal ligation and puncture (CLP) method in mice with the goal of creating a model that concurrently displays all the characteristics of PICS. We observed that, after eight days, mice that survive the CLP develop persistent inflammation with significant myelopoiesis in the bone marrow and spleen. These mice also demonstrate ongoing immune suppression, as evidenced by the decreased total and naïve splenic CD4 and CD8 T cells with a concomitant increase in immature myeloid cells. The mice further display significant weight loss and decreased muscle mass, indicating a state of ongoing catabolism. When PICS mice are challenged with intranasal Pseudomonas aeruginosa, mortality is significantly elevated compared to sham mice. This mortality difference is associated with increased bacterial loads in the lung, as well as impaired neutrophil migration and neutrophil dysfunction in the PICS mice. Altogether, we have created a sepsis model that concurrently exhibits PICS characteristics. We postulate that this will help determine the mechanisms underlying PICS and identify potential therapeutic targets to improve outcomes for this patient population.

In the acute-care setting, it is widely accepted that elderly patients have increased morbidity and mortality compared with young healthy patients. The reasons for this, however, are largely unknown. Although animal modeling has helped improve treatment strategies for young patients, there are a scarce number of studies attempting to understand the mechanisms of systemic insults such as trauma, burn, and sepsis in aged individuals. This review aims to highlight the relevance of using animals to study the pathogenesis of these insults in the aged and, despite the deficiency of information, to summarize what is currently known in this field.

During sepsis, the early innate response and inflammatory cytokine cascade are associated with activation of the coagulation cascade. Acute hypercoagulability can contribute to lethal sequela of vascular thrombosis, tissue ischemia, and organ failure. We investigated if amitriptyline (AMIT), an antidepressant drug with a number of anti-inflammatory effects, could ameliorate sepsis in a murine model of sepsis - cecal ligation and puncture (CLP). We hypothesized that AMIT treatment would reduce inflammation and mitigate sepsis-induced coagulopathy. Coagulation was measured using thromboelastometry and ferric chloride-induced carotid artery thrombosis. Our findings demonstrate a dynamic early hypercoagulability, followed by delayed hypocoagulability in septic mice. However, septic mice treated with AMIT were unaffected by these coagulation changes and exhibited a coagulation profile similar to sham mice. TNFα was markedly elevated in septic mice, but decreased in AMIT-treated mice. Exogenous administration of recombinant TNFα in naïve mice recapitulated the acute sepsis-induced hypercoagulability profile. Following sepsis and endotoxemia, peritoneal macrophages were the predominant source of TNFα expression. AMIT treatment significantly decreased macrophage TNFα expression and blunted M1 polarization. Altogether, during polymicrobial sepsis, AMIT treatment suppressed macrophage TNFα expression and the M1 phenotype, mitigating an initial hypercoagulable state, and protecting septic mice from delayed hypocoagulability. We propose that AMIT treatment is a promising therapeutic approach in the treatment of sepsis-associated coagulopathy and prevention of acute thromboembolic events or delayed bleeding complications.