Interplay between inflammation and degeneration: Using inclusion body myositis to study “neuroinflammation”

In primary inflammatory or autoimmune neurological disorders, such as primary or secondary progressive multiple sclerosis and chronic inflammatory neuropathies and myopathies, the chronic persistent inflammation leads to degeneration and irreversible cell loss. In other disorders considered neurodegenerative, such as Alzheimer’s disease or amyotrophic lateral sclerosis, there is “neuroinflammation” characterized by gliosis, macrophage activation, and cytokine upregulation. Although in most of these conditions inflammatory mediators coexist even from the outset with cell stress and degeneration, the interrelationship between inflammatory and degeneration-associated molecules has not been studied in vivo, and the clinically relevant markers connected with disease progression remain unclear. Perhaps one of the typical human neurological disorders in which inflammation and degeneration coexist from the outset is inclusion body myositis (IBM), the most common acquired myopathy for individuals older than 50 years. The muscles of IBM patients have the following characteristics: (1) clonal expansion of CD8 cells that invade major histocompatibility complex class I (MHC-I)–expressing muscle fibers; (2) persistent upregulation of cytokines, chemokines, adhesion molecules, and MHC-I, which induces cell stress; (3) vacuolization; (4) mitochondrial and nuclear abnormalities; (5) promiscuous deposits of degenerationassociated molecules, identical to those seen in Alzheimer’s disease, such as -amyloid, tau, ubiquitin, presenilin, -synuclein, and apolipoprotein E; and (6) involvement of the ubiquitin-proteasome system, including the disposal of unwanted proteins by macroautophagy, as seen in neurodegenerative disorders. Because of these features, the IBM muscle is a useful tool to investigate in vivo the interplay between inflammatory and degenerative molecules. Toward this goal, Kitazawa and colleagues’ study is a significant contribution that complements recent work from our laboratory. Using an IBM-transgenic mouse model, the authors found that acute and chronic inflammation induced by lipopolysaccharide (LPS) increased the steady-state level of amyloid precursor protein and phosphorylated tau in skeletal muscle by inducing glycogen synthase kinase-3 (GSK3 ), a tau kinase. The cytokines interleukin-1 , interleukin-6, and tumor necrosis factorupregulated GSK-3 , whereas antibodies against them effectively attenuated the inflammation-induced tau phosphorylation. The GSK inhibitor, lithium, had a similar effect. The authors conclude that suppression of inflammation in IBM may slow disease progression. The findings are interesting and support previous studies even though they are only indirectly related to human IBM for several reasons. First, the MCK-amyloid precursor protein mouse is not a satisfactory IBM model because the muscles have atypical histology, no inflammation, and minimal weakness; second, lipopolysaccharide is an artificial and transient inflammatory inducer; and third, the myofibers in MCK-amyloid precursor protein mice express MHC-I only transiently after lipopolysaccharide administration. These limitations do not, however, diminish the impact of Kitazawa and colleagues’ observations. To the contrary, the mice offer a strong glimpse on the magnitude of alterations occurring in the human muscle where inflammation is profound, MHC-upregulation persistent, vacuolization prominent, and -amyloid deposition pronounced. The scholars in the field of IBM are divided into two camps; one believes that inflammation is the primary culprit and liken the disease to primary progressive multiple sclerosis, which, like IBM, does not respond to immunotherapies; the other considers the disease degenerative and the inflammation secondary to accumulation of -amyloid–driven molecules, one of which may be driving antigen-specific T cells. We have favored the autoimmune hypothesis for the following reasons: (1) IBM is frequently seen with autoimmune disorders and increasingly with human immunodeficiency virus and Human T cell Lymphotropic Virus infection; (2) T-cell invasion of nonnecrotic fibers is found early and in greater frequency than the Congo red–positive fibers; (3) the cytotoxic T cells, at the immunological synapses, do not recognize amyloidrelated proteins as antigens; (4) the cytokine-induced upregulation of MHC-I occurs early and is capable of triggering cell stress and degeneration; and (5) cytokines, especially IL1 , can induce amyloid aggregates (6). Most importantly, endomysial inflammation alone can cause muscle destruction and clinical weakness, as seen in polymyositis; whether the tiny -amyloid deposits are sufficient alone to trigger muscle degeneraEDITORIAL