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Innate Immunity and Inflammation in NAFLD/NASH

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Abstract

Inflammation and hepatocyte injury and death are the hallmarks of nonalcoholic steatohepatitis (NASH), the progressive form of nonalcoholic fatty liver disease (NAFLD), which is a currently burgeoning public health problem. Innate immune activation is a key factor in triggering and amplifying hepatic inflammation in NAFLD/NASH. Thus, identification of the underlying mechanisms by which immune cells in the liver recognize cell damage signals or the presence of pathogens or pathogen-derived factors that activate them is relevant from a therapeutic perspective. In this review, we present new insights into the factors promoting the inflammatory response in NASH including sterile cell death processes resulting from lipotoxicity in hepatocytes as well as into the altered gut-liver axis function, which involves translocation of bacterial products into portal circulation as a result of gut leakiness. We further delineate the key immune cell types involved and how they recognize both damage-associated molecular patterns or pathogen-associated molecular patterns through binding of surface-expressed pattern recognition receptors, which initiate signaling cascades leading to injury amplification. The relevance of modulating these inflammatory signaling pathways as potential novel therapeutic strategies for the treatment of NASH is summarized.

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Abbreviations

NAFLD:

Nonalcoholic fatty liver disease

NASH:

Nonalcoholic steatohepatitis

ROS:

Reactive oxygen species

RIP1 and RIP3:

Receptor protein kinases 1 and 3

TNF-R1:

Tumor necrosis factor receptor-1

DAMPs:

Damage-associated molecular patterns

PRRs:

Pattern recognition receptors

PAMPs:

Pathogen-associated molecular patterns

HMGB1:

The high-mobility group box 1

LPS:

Lipopolysaccharide

TNF-α:

Tumor necrosis factor-alpha

IL:

Interleukin

TLRs:

Toll-like receptors

KCs:

Kupffer KCs

HSC:

Hepatic stellate cells

DCs:

Dendritic cells

NLRs:

Nucleotide oligomerization NOD-like receptors domain

CCL2 and CCL5:

C-C motif ligand 2 and 5

PPAR-δ:

Peroxisome proliferator activator receptor delta

CX3CR1:

Fractalkine receptor

NK:

Natural killer

NKT:

Natural killer T

IB:

Intestinal barrier

GLP-1:

Glucagon-like peptide 1

FGF19:

Fibroblast growth factor-19

IL-4:

Interleukin-4

IFN-γ:

Interferon-gamma

PDGF:

Platelet-derived growth factor

NEU:

Neutrophils

SAMs:

Scar-associated macrophages

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Acknowledgments

This work was funded by NIH grants R01 DK082451 and U01 AA022489 to A.E.F. and by grants from the Fondo Nacional de Desarrollo Cientıfico y Tecnologico (FONDECYT 1150327 to M.A. and FONDECYT PD3140396 to D.C.) and the Comision Nacional de Investigacion Cientıfica y Tecnologica (grant PFB 12/2007, Basal Centre for Excellence in Science and Technology, M.A.), both from the Government of Chile. A.K. received support from the Millennium Institute on Immunology and Immunotherapy, Santiago Chile. We thank Nicolas Triantafilo, MD, for assistance in providing the figure for this article.

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Authors and Affiliations

  1. Departmento de Gastroenterología, Escuela de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile

    Marco Arrese & Daniel Cabrera

  2. Departamento de Ciencias Químicas y Biológicas, Facultad de Salud, Universidad Bernardo O Higgins, Santiago, Chile

    Daniel Cabrera

  3. Millenium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile

    Alexis M. Kalergis

  4. Department of Pediatrics, University of California San Diego (UCSD), San Diego, CA, USA

    Ariel E. Feldstein

  5. Rady Children’s Hospital, San Diego, CA, USA

    Ariel E. Feldstein

  6. Division of Pediatric Gastroenterology, Hepatology, and Nutrition, UCSD, 3020 Children’s Way, MC 5030, San Diego, CA, 92103-8450, USA

    Ariel E. Feldstein

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  1. Marco Arrese
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  2. Daniel Cabrera
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  4. Ariel E. Feldstein
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Correspondence to Ariel E. Feldstein.

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Arrese, M., Cabrera, D., Kalergis, A.M. et al. Innate Immunity and Inflammation in NAFLD/NASH. Dig Dis Sci 61, 1294–1303 (2016). https://doi.org/10.1007/s10620-016-4049-x

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