Overview

Cytokines are produced by a wide variety of cells and regulate immune cell activation and infiltration in affected tissues. The most predominantly reported cytokines in myositis include pro-inflammatory cytokines such as IL-1α, IL-1β, TNF-α and transforming growth factor (TGF)-β (1)

The NF-kB pathway is one of the predominant regulators of a variety of essential biological processes, including inflammation. In myositis both immune and skeletal muscle cells modulate inflammation via the NF-kB pathway. NF-kB is a ubiquitous transcription factor composed of a heterodimer with two subunits, p65 (Rel A)/c-Rel/Rel B and p50. NF-kB is kept sequestered in an inactive form in the cytoplasm through an interaction with its specific inhibitor IkBα. When a stimulus is received, the upstream IkB kinase (IKK) phosphorylates IkBα, leading to its proteosomal degradation. Free NF-kB is then translocated to the nucleus, where it regulates the expression of several pro-inflammatory genes, including TNF-α and IL-1β. We have previously demonstrated that unusual overexpression of MHC class I on the muscle fibers of myositis muscle can also cause the activation of NF-kB, including the induction of ER stress response pathways .Further evidence suggests that downstream NF-kB target genes such as intercellular adhesion molecules (ICAM) and MCP-1 are also highly up-regulated in myositis muscle. Several groups have independently validated NF-kB activation in inflammatory myopathies and its role in modulating the immune response, myogenesis and muscle repair .(1)
 

NF-kB and NLR-inflammasome activation in skeletal muscle.

NLR-inflammasomes are intracellular multi-protein complexes formed by the adaptor molecule apoptosis-associated speck-like protein with caspase recruiting domain (ASC), caspase-1, and the members of the NLR family such as NLRP1, NLRP3 and NLRC4. NLR-inflammasomes are also activated by PAMPs/DAMPs and result in secretion of the pro-inflammatory cytokines. Although the process is not yet completely understood, the general consensus is that inflammasomes are activated through three signaling pathways: 1) potassium efflux, 2) generation of reactive oxygen species, and 3) production of cathepsin B .More recently, our group has shown that normal primary skeletal muscle cells are capable of secreting IL-1β in response to combined treatment with TLR-4 ligand, lipopolysaccharide and P2X7 receptor agonist, ATP, suggesting that not only immune cells but also muscle cells can actively participate in inflammasome formation implicating skeletal muscle cells in perpetuating a pro-inflammatory environment. (2,3)
 

Dendritic cells connect the innate and adaptive arms of the immune system

There is clear evidence that innate and adaptive immune cytokines influence each other. For instance, IL-18 stimulates the secretion of IFN-γ and TNF-α via a Th1-mediated response .Similarly, IL-1β binds to IL-1 receptor on dendritic cells and produces IL-23 via a Th17-mediated response, and IL-33 binds to IL-1 receptor-related protein (ST2) and enhances the secretion of IL-10 and IL-13 through Th2-mediated responses . IL-33 also induces the secretion of IL-13, IL-10 and TGF-β by stimulating mast cells and T-reg cells. These interactions through cytokines highlight that innate and adaptive immune processes are interrelated and studies to understand their role in muscle disease pathogenesis are imminent.(4,5)
 

Inflammatory pathway

The inflammasome pathway is connected to the TLR signaling pathway. TLR-2/4 signaling results in the synthesis of pro-IL-1β, and inflammasomes process pro-IL-1β into mature IL-1β; signaling by released extracellular ATP via P2X7 receptors (DAMP signaling) facilitates the secretion of mature IL-1β from the skeletal muscle cells . Another recent study has characterized the mechanism of IL-1β secretion following respiratory syncytial virus (RSV) infection of airways . This study underscored the requirement for the (TLR-2)/MyD88/NF-κB pathway prior to the activation of the inflammasomes and subsequent IL-1β release in the affected tissue . In sum, these findings suggest a possible cross-talk between TLRs and inflammasome pathways. In myositis, the activation of inflammasomes and the subsequent release of cytokines in affected muscle have not yet been investigated; however, enhanced expression of both TLRs and IL-1α and IL-1β in areas surrounded by inflammatory cells suggest that TLR-inflammasome pathway is active in myositis muscle .(6)
 

What’s next

Therefore, it is possible that the cytokines released from the activation of inflammasome pathways can stimulate innate and adaptive immune cells and further augment the secretion of either pro-inflammatory or anti-inflammatory cytokines, so further investigations needs to be performed to find a way to block this pathway in order to improve the palliative treatment of the immune disease.

 

Footnotes

1. Wang H. NF-kappaB regulation of YY1 inhibits skeletal myogenesis through transcriptional silencing of myofibrillar genes. Mol Cell Biol. 2007, 27: 4374-4387. 10.1128/MCB.02020-06.PubMed CentralPubMed

2. Bakkar N.IKK/NF-kappaB regulates skeletal myogenesis via a signaling switch to inhibit differentiation and promote mitochondrial biogenesis. J Cell Biol. 2008, 180: 787-802. 10.1083/jcb.200707179.PubMed CentralPubMed

3. Creus KK .Distribution of the NF-kappaB complex in the inflammatory exudates characterizing the idiopathic inflammatory myopathies. Ann N Y Acad Sci. 2009, 1173: 370-377. 10.1111/j.1749-6632.2009.04874.x.PubMed

4. Rawat R.Inflammasome up-regulation and activation in dysferlin-deficient skeletal muscle. Am J Pathol. 2010, 176: 2891-2900. 10.2353/ajpath.2010.090058.PubMed CentralPubMed

5. Segovia J.TLR2/MyD88/NF-kappaB pathway, reactive oxygen species, potassium efflux activates NLRP3/ASC inflammasome during respiratory syncytial virus infection. PLoS One. 2012, 7: e29695-10.1371/journal.pone.0029695.PubMed CentralPubMed

6. Tournadre A.Th1 and Th17 balance in inflammatory myopathies: interaction with dendritic cells and possible link with response to high-dose immunoglobulins. Cytokine. 2009, 46: 297-301. 10.1016/j.cyto.2009.02.013.PubMed