Focus
Authors: Scott L. Friedman
Journal: Journal of Hepatology (2011)

Increasing attention is focused on the nature and origins of chronic inflammation in patients with morbid obesity and non-alcoholic fatty liver disease (NAFLD). Smoldering inflammation without an obvious precipitant is also recognized in a range of related disorders that includes atherosclerosis, dementia, type 2 diabetes and even cancer [1Vandanmagsar B. Youm Y.H. Ravussin A. Galgani J.E. Stadler K. Mynatt R.L. et al.The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance.Nat Med. 2011; 17: 179-188Crossref PubMed Scopus (1837) Google Scholar, 2Yang H. Youm Y.H. Vandanmagsar B. Ravussin A. Gimble J.M. Greenway F. et al.Obesity increases the production of proinflammatory mediators from adipose tissue T cells and compromises TCR repertoire diversity: implications for systemic inflammation and insulin resistance.J Immunol. 2010; 185: 1836-1845Crossref PubMed Scopus (341) Google Scholar]. Studies of this ‘autoinflammation’ have zeroed in on an intracellular multi-protein scaffold known as the inflammasome, whose primary function is to activate an inflammatory cascade as part of the innate immune response’s cytosolic surveillance [3Schroder K. Tschopp J. The inflammasomes.Cell. 2010; 140: 821-832Abstract Full Text Full Text PDF PubMed Scopus (4231) Google Scholar, 4Bauernfeind F. Ablasser A. Bartok E. Kim S. Schmid-Burgk J. Cavlar T. et al.Inflammasomes: current understanding and open questions.Cell Mol Life Sci. 2011; 68: 765-783Crossref PubMed Scopus (293) Google Scholar]. Activation of the inflammasome culminates in the auto-catalytic cleavage of caspase-1 that facilitates processing and secretion of the inflammatory cytokines interleukin (IL)-1β and IL-18. In other words, increased IL-1β is among the most important consequences of inflammasome activation. While originally characterized in classic immune cells, it is now clear that the inflammasome is also present in non-immune cells, including hepatocytes and hepatic stellate cells, as well as hepatic macrophages and dendritic cells. Inflammasomes are classified by the specific type of pattern recognition receptors (PRRs) within the inflammasome that have evolved to distinguish among a range of stimuli (e.g., bacterial or viral proteins, or crystals). Among these, for example, the Nod-like receptor (NLR) family of innate immune cell sensors, specifically NLRP3 (also known as NALP3 or cryopyrin), has been linked to obesity-induced inflammation [[1]Vandanmagsar B. Youm Y.H. Ravussin A. Galgani J.E. Stadler K. Mynatt R.L. et al.The NLRP3 inflammasome instigates obesity-induced inflammation and insulin resistance.Nat Med. 2011; 17: 179-188Crossref PubMed Scopus (1837) Google Scholar]. IL-1, which was first described as an endogenous pyrogen in the 1940’s, actually consists of two structurally similar but distinct proteins, IL-1α and IL-1β [[5]Gabay C. Lamacchia C. Palmer G. IL-1 pathways in inflammation and human diseases.Nat Rev Rheumatol. 2010; 6: 232-241Crossref PubMed Scopus (579) Google Scholar]. IL-1β is implicated in a range of inflammatory diseases and thus efforts to antagonize the protein are an attractive therapeutic strategy. This prospect is underscored by a recent study by Kamari et al. published in the Journal [[6]Kamari Y. Shaish A. Vax E. Shemesh S. Kandel-Kfir M. Arbel Y. et al.Lack of interleukin-1alpha or interleukin-1beta inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice.J Hepatol. 2011; 55: 1086-1094Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar], and summarized in a lovely editorial [[7]Tilg H. Moschen A.R. IL-1 cytokine family members and NAFLD: neglected in metabolic liver inflammation.J Hepatol. 2011; 55: 960-962Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar], in which mice lacking either IL-1α or IL-1β had markedly reduced steatohepatitis and fibrosis when fed an atherogenic diet. Interestingly, nature has already generated its own IL-1β antagonist, the IL-1 receptor antagonist (IL-1Ra). IL-1Ra was identified as the first naturally occurring cytokine receptor antagonist and was initially described as an acute-phase protein. It competes for binding of IL-1 to its cognate receptor, yet it does not elicit signaling. Of the four IL-1Ra isoforms, one is secreted (sIL-1Ra), whereas the other three remain in the cell unless they are liberated when the cell dies. Both knockout mice and children with IL-1Ra deficiency have marked autoinflammation, attesting to the physiologic importance of the molecule in preserving immune homeostasis. In this month’s issue of the Journal, the study by Pihlajamaki and colleagues from Finland identifies elevated sIL-R1a as an independent marker of human NASH severity. They correlated serum levels of sIL-R1a with liver histology in 119 morbidly obese men undergoing bariatric surgery, and additionally correlated serum levels of the molecule with ALT levels among 6447 men from a cross-sectional cohort. In those undergoing surgery, a decrease in sIL-R1a correlated with improvement in lobular inflammation. The investigators used this information to generate a refined NAFLD liver inflammation score whose performance exceeded existing scoring systems. The findings complement a recent study from Austria, in which IL-Ra1 levels also dropped after bariatric surgery, but the latter study additionally determined that the bulk of IL-R1a mRNA expression was in adipose, not the liver [[8]Moschen A.R. Molnar C. Enrich B. Geiger S. Ebenbichler C.F. Tilg H. Adipose and liver expression of interleukin (IL)-1 family members in morbid obesity and effects of weight loss.Mol Med. 2011; 17: 840-845Crossref PubMed Scopus (137) Google Scholar]. The single-site Finnish study is somewhat limited by the inclusion only of men, the review of biopsies by a single pathologist, and the lack of correlation of sIL-1Ra with hepatocyte ballooning, the most characteristic histologic feature of NASH. Still, it is novel and intriguing. The much bigger – and completely obscure – issue is the underlying pathophysiology of sIL-1Ra elevation in the context of systemic autoinflammation and NASH. IL-1Ra is an anti-inflammatory molecule, yet its elevation is a marker of inflammation in NASH and other inflammatory diseases. Is the elevation of sIL-1Ra in obesity and NASH a counter-regulatory response that is ineffective in attenuating the autoinflammatory cascade? In severe autoinflammatory diseases a recombinant IL-1 receptor antagonist, anakinra, is a highly effective therapy so that sIL-1Ra should be attenuating inflammation in fatty liver disease as well [[9]Ombrello M.J. Kastner D.L. Autoinflammation in 2010: expanding clinical spectrum and broadening therapeutic horizons.Nat Rev Rheumatol. 2011; 7: 82-84Crossref PubMed Scopus (21) Google Scholar]. Also, are the signals driving hepatic inflammation and their counter-regulators largely derived from adipose rather than the liver? On the one hand, the earlier study by Kamari has implicated the liver as the key source of IL-1α [[6]Kamari Y. Shaish A. Vax E. Shemesh S. Kandel-Kfir M. Arbel Y. et al.Lack of interleukin-1alpha or interleukin-1beta inhibits transformation of steatosis to steatohepatitis and liver fibrosis in hypercholesterolemic mice.J Hepatol. 2011; 55: 1086-1094Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar], whereas adipose may provide the bulk of IL-1β. There is precedent for exactly a scenario wherein a beneficial protein circulates at high levels in the face of ongoing disease in studies of leptin, the adipogenic hormone that promotes weight loss and increased metabolic activity. Obese patients are typically hyperleptinemic because serum levels are directly correlated with adipose mass, yet these patients are effectively leptin-resistant, much like type 2 diabetics are relatively insulin-resistant with high circulating insulin levels. Are obese patients similarly resistant to sIL-1Ra? If so, what is the mechanism that confers this resistance? It’s obvious that we are barely scratching the surface in understanding the role of IL-1 signaling and the inflammasome in hepatic physiology and disease. Moreover, recent experimental models highlight the importance of the inflammasome not only in inflammation but also in tissue fibrosis [[10]Artlett C.M. Sassi-Gaha S. Rieger J.L. Boesteanu A.C. Feghali-Bostwick C.A. Katsikis P.D. The inflammasome activating caspase 1 mediates fibrosis and myofibroblast differentiation in systemic sclerosis.Arthritis Rheum. 2011; 63: 3563-3574Crossref PubMed Scopus (137) Google Scholar] and hepatic stellate cell activation [[11]Watanabe A. Sohail M.A. Gomes D.A. Hashmi A. Nagata J. Sutterwala F.S. et al.Inflammasome-mediated regulation of hepatic stellate cells.Am J Physiol Gastrointest Liver Physiol. 2009; 296: G1248-1257Crossref PubMed Scopus (178) Google Scholar]. Nonetheless, large clinical studies like that of Pihlajamaki and colleagues help frame the key questions to be answered experimentally using animal models and molecular approaches. The search to clarify the inflammasome’s role in liver disease is just beginning. The author declared that he does not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.