Idiopathic inflammatory myopathies: pathogenic mechanisms of muscle weakness

Abstract

Idiopathic inflammatory myopathies (IIMs) are a heterogenous group of complex muscle diseases of unknown etiology. These diseases are characterized by progressive muscle weakness and damage, together with involvement of other organ systems. It is generally believed that the autoimmune response (autoreactive lymphocytes and autoantibodies) to skeletal muscle-derived antigens is responsible for the muscle fiber damage and muscle weakness in this group of disorders. Therefore, most of the current therapeutic strategies are directed at either suppressing or modifying immune cell activity. Recent studies have indicated that the underlying mechanisms that mediate muscle damage and dysfunction are multiple and complex. Emerging evidence indicates that not only autoimmune responses but also innate immune and non-immune metabolic pathways contribute to disease pathogenesis. However, the relative contributions of each of these mechanisms to disease pathogenesis are currently unknown. Here we discuss some of these complex pathways, their inter-relationships and their relation to muscle damage in myositis. Understanding the relative contributions of each of these pathways to disease pathogenesis would help us to identify suitable drug targets to alleviate muscle damage and also improve muscle weakness and quality of life for patients suffering from these debilitating muscle diseases.

Figure 1

Innate immune mechanisms of muscle damage in myositis. Skeletal muscle undergoes continuous injury and repair in response to a variety of physiological (exercise) and pathological (infection) insults and releases damage-associated molecular patterns (DAMPs) from dead and damaged cells (Step 1). DAMPs initiate innate immune signaling by binding to surface or endogenous TLRs on various cells including skeletal muscle fiber, infiltrating macrophages (Mϕ), myeloid dendritic cells (mDCs), plasmacytoid DCs (pDCs), capillaries, and other cell types such as fibroblasts (Step 2) [4-6]. This innate signaling through TLR and other innate immune receptors induces the secretion of pro-inflammatory cytokines and chemokines [e.g., Type 1 interferons (IFN-α, IFN-β), TNF-α, IL-1, IL-12 and IFN-γ] into the microenvironment (Step 3). These cytokines and DAMPs bind to their respective receptors on muscle and capillaries [e.g., tumor necrosis factor receptor (TNFR), IL-1 receptor (IL-1R)] and exert downstream effects (Step 4) [7-10]. Cytokines and/or chemokines directly cause damage to capillaries and hypoxia in the affected muscle. Cytokines such as TNF-α can directly induce cell death of muscle cells, while NF-kB is known to block MyoD and inhibit formation of the new muscle fibers [11-13]. Thus this pathway not only effectively enhances the death of existing muscle fibers but also inhibits formation of new muscle fibers leading to the loss of skeletal muscle mass and weakness in these disorders.

Figure 2

Adaptive immune mechanisms of muscle damage in myositis. DAMP signaling through TLRs in the innate immune cells activates various antigen-presenting cells (APC) in the muscle (shown in Figure 1). These APCs activate CD4 T-cells via MHC class I and CD8 T-cells initiate autoantigen specific T-cell responses (Step 1) [26]. Activated CD4+ T-cells differentiate into T-helper (Th)-17 (TGF-β), Th2 (IL-4), and Th1(IL-12) effector T-cells in the presence of respective cytokines, and in turn produce discrete sets of cytokines that affect a variety of cell types (Step 2) [53]. Th1 cells through IFN-γ generate M1 macrophages, which secrete TNF-α, IL-6 and IL-1, and damage cells. Th2 cells, through IL-4, TGFβ and IL-10, generate M2 macrophages that are known to help tissue repair and remodeling in the affected tissues [54,55]. Th2 cells also help stimulate B-cell maturation and differentiation into plasma cells that produce autoantibodies and further initiate complement mediated damage to capillaries and induce hypoxia (Step 3). Cytotoxic CD28^−/− T-cells and regulatory T-cells (Tregs) reduce inflammation and tissue damage by inhibiting the function of antigen presenting cells and T-effector cells [56,57]. It is also known that activated CD8 T-cells differentiate into cytotoxic T-cells (CTL) and exert cytotoxic effects on the affected muscle through secretion of perforin-1 and granzyme-B enzymes (Step 4) [58]. Thus the myositis muscle microenvironment is complex, with both tissue repair and tissue-damaging mechanisms in play at all times. The relative ratios of these pathways determine the disease severity and progression.

Figure 3

Non-immune mechanisms of muscle damage and weakness. MHC class I overexpression on myofibers make muscle susceptible for CD8 T-cell mediated cytotoxicity as well as susceptible to endoplasmic reticulum stress-induced cell death. MHC class I accumulation in endoplasmic reticulum induces stress responses (unfolded protein response and endoplasmic reticulum overload response (EOR)) [27,94-98]. Induction of EOR activates downstream NF-kB pathway leading to pro-inflammatory cytokine production and reduction in new muscle formation by inhibiting MyoD. It also induces cell death mechanisms via the activation of caspases 12, 3 and 7 as well as calpain pathways (Step A) [27]. Innate cytokines, mitochondrial energy-related metabolic pathways, and purine nucleotide pathways are interconnected in myositis muscle. For instance, IL-1 reduces the production of nitric oxide (NO) and causes mitochondrial dysfunction by affecting NADH reductase and succinate CoQ [99-102]. Likewise, unknown cytokines reduce expression of rate-limiting enzymes of the purine nucleotide cycle and of AMPD1 in skeletal muscle. This acquired deficiency of APMD1 causes muscle weakness and fatigue in myositis (Step B) [103]. Activation of TRAIL forms autophagosomes and induces autophagy (Step C) [104]. TLR signaling leads to inflammasome activation, IL-1 secretion and pyroapoptosis in the affected muscle. There are active interactions between autophagy, ER stress, and inflammasome and purine nucleotide pathways. Even though all these pathways are interconnected, we have represented them as linear pathways in this illustration for easier understanding. Thus, several non-immune and metabolic pathways directly and indirectly contribute to muscle weakness and damage in myositis.