The inflammatory response initiated by stimulation with LPS shows distinct stages that begin with induction of a pro-inflammatory response and classical macrophage activation. This is followed by expression of anti-inflammatory cytokines and the initiation of negative feedback pathways that down-regulate pro-inflammatory signaling pathways. The overall result is repair, resolution and return to tissue homeostasis. Chronic inflammation upsets the checks and balances used by a tissue to control innate immune responses and results in the simultaneous presence of pro-inflammatory and repair processes. This imbalance could be generated by multiple factors such as failure of inherent immune shutdown mechanisms leading to maintained production of cytotoxic agents, or prolonged and inappropriate induction of tissue remodeling and repair mechanisms that initiate damage to normal tissue structure. We have found a mixture of pro-inflammatory and repair genes in gene expression profiles from brain samples of AD patients compared to age-matched normal individuals. See Alzheimer's Data Figure

In this case, NOS2 mRNA levels are not changed while mRNA of both pro-inflammatory cytokines TNFa and matrix repair factors AG1 and chitinase 3- like 1 (CH3L1) are increased. We suggest that inflammation in AD may represent a complex chronic immune activation state that represents the brain's response to a persistent, unresolved immune stimulus. The stimulus is likely to be Aβ.

The expression of both pro-inflammatory and anti-inflammatory cytokines/repair factors in AD suggests that immune activation in AD has features of both classical and alternative activation. Innate immune cells such as macrophages are highly pleiotropic and show distinct states of activation that have been recently described in detail by Simon Gordon. Classical macrophage activation as observed in a pro-inflammatory state is characterized by increased levels of mRNA and protein for TNFa, IL-6, IL-12, IL-1β and NOS2. Macrophages that demonstrate alternative activation are associated with anti-inflammatory cytokines, such as IL-4 and TGFβ, and factors involved in repair and tissue reconstruction (resolution of the wound), such as AG1, mannose receptor (MRC), and Chitinase-3-like-1 (Ym1 in rodents). Interestingly, MHCII expression is increased in alternatively activated as well as in classically activated macrophages and thus does not serve as a distinguishing feature of a pro-inflammatory state. NOS2 expression, however, is low during an alternative activation state . Multiple factors, such as high expression of arginase 1 and production of TGFβ, work in concert to suppress NOS2 mRNA, iNOS activity and NO production. For example, arginase 1 activity competes for arginine (see above insert), the sole substrate for iNOS, while TGFβ suppresses NOS2 expression. The presence of alternative activation in AD thus implies that NOS2 mRNA expression and iNOS activity may be downregulated. The integrated effects of the local macrophage activation stage may help to explain why NOS2 mRNA and iNOS expression levels have been found to be highly variable in AD brain compared to age-matched controls. Click to see a table that defines the gene profile for alternative activation.

Generally viewed as immunosuppressive, alternatively activated macrophages promote tissue repair and extracellular matrix remodeling. However, they may also contribute to disease processes in a complex way. For example, alternatively activated alveolar macrophages contribute to the fibrotic lesion in idiopathetic pulmonary fibrosis and in the liver fibrosis associated with Schistosoma mansoni. In fact, the schistosoma ova parasite initiates a chronic immune response in the liver that begins with a rapid but transient pro-inflammatory response involving TNFa and other cytotoxic cytokines. This short phase is followed by a long repair phase that is driven principally by alternative activated macrophages but results in fibrosis and other aberrant repair. Withdrawal of cytokines such as IL4, which help to maintain the alternative activation state, increases the life span of parasite infected animals and removes the tissue protection against self-toxic innate immune events. These changes are highly reminiscent of AD pathology.

Thus, we believe that the current view of inflammation in AD is inaccurate and does not truly consider the complexity of the innate immune response nor its chronic nature. Part of the problem has been the lack of a mouse model showing pathology that truly represents AD, especially neuronal loss. These inadequacies, however, have not stopped the development and testing of a number of therapeutics based on blocking inflammation in patients with AD. Many of these therapeutics have essentially failed to be useful. We have multiple ongoing projects investigating these complexities of inflammation in AD.

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