Expression of IL‐37 Correlates With Immune Cell Infiltrate and Fibrosis in Pediatric Autoimmune Liver Diseases

Abstract

Objectives:The activation of innate immune mechanisms is key for chronic liver injury. Interleukin-37 (IL-37) is a profound inhibitor of innate and adaptive immune responses, and its overexpression protects mice from liver inflammation and fibrosis. Here, we characterize the hepatic inflammatory infiltrate and expression of IL-37 in children with autoimmune liver diseases.Methods:We compared the inflammatory microenvironment of the liver in a retrospective cohort of children with primary sclerosing cholangitis (PSC), autoimmune sclerosing cholangitis (ASC) and autoimmune hepatitis (AIH) by immunohistochemistry. The expression of IL-37 was quantified in liver parenchyma and portal tracts. Double immunofluorescence was used for detection of IL-37 in specific cell types and colocalization with Smad3.Results:AIH is characterized by a dense lymphoplasmacytic infiltrate whereas ASC shows high numbers of granulocytes in portal tracts. IL-37 expression correlates positively with liver inflammation and fibrosis, the number of infiltrating immune cells and serum markers for hepatic inflammation. IL-37 is mainly expressed in hepatocytes, cholangiocytes and infiltrating immune cells. Double staining revealed IL-37 positivity in T helper and regulatory T cells (Treg), Kupffer (KC) and hepatic stellate cells (HSC). IL-37 colocalizes with intranuclear pSmad3L in areas of liver inflammation.Conclusions:Pediatric ASC separates from PSC and AIH by a granulocyte-rich portal infiltrate. Upregulation of IL-37 with liver injury, the expression in Treg as well as KC and HSC and the colocalization of IL-37 with pSmad3L in cholangiocytes and hepatocytes suggest a modulating role to limit hepatic inflammation and fibrosis in pediatric autoimmune liver diseases.

Fötal Gelişim Süresince Sığır Karaciğerinde İnterlökin-37 ve Reseptörünün İmmunohistokimyasal Lokalizasyonu

“…Bununla birlikte insan karaciğerinde IL-37 ekspresyonunun normal dokularda çok düşük düzeyde olduğu ve inflamatuar uyarıya yanıt olarak belirgin şekilde arttığı gösterilmiştir (24). Yine insanlarda (çocuk) yapılan araştırmada IL-37'nin ana kaynağı olarak hepatositlerin olabileceği ve bu hücrelerde ekspresse olmasının yanı sıra kolanjiyositler ve portal yollarda bulunan bağışıklık hücrelerinde (yardımcı ve düzenleyici T hücreleri, kupffer ve hepatik yıldız hücreleri) de lokalize olduğunu bildirmişlerdir (25). IL-37'nin farelerde karaciğerin kupffer ve hepatik yıldız hücrelerinde ekspresse olduğu, karaciğer inflamasyonu ve fibrozisi durumunda IL-37 ekspresyonunun arttığı ve bu durumlara karşı karaciğer hücrelerini korumaya çalıştığı ifade edilmiştir (26).…”

“…Bizim çalışmamızda da diğer çalışmalarda (24,25,26,27) olduğu gibi IL-37 immunoreaktivitesinin gebeliğin ikinci ve üçüncü dönemlerinde hepatositlerde pozitif olduğu ancak birinci dönemde immunoreaktivite'nin şekillenmediği görülmüştür. Böylece IL-37'nin gebeliğin ilk dönemlerinde hepatositlerin fonksiyonel gelişimi üzerine katkı sağlamadığını düşündürdü.…”

Research Progress on the Role and Mechanism of IL-37 in Liver Diseases

“… 77 Intracellular IL-37 has been demonstrated to regulate liver fibrosis in two distinct ways: (1) by co-localizing with pSmad3L in cholangiocytes and hepatocytes, directly targeting fibrotic pathways, and (2) by restricting infiltrating lymphocytes, macrophages, and KCs to release proinflammatory and profibrotic cytokines to downregulate liver inflammation and subsequent HSC activation. 78 79 Therefore, IL-37-dependent mechanisms can be targeted to treat inflammatory and fibrotic liver diseases ( Fig. 3 ).…”

IL-37 Ameliorates Renal Fibrosis by Restoring CPT1A-Mediated Fatty Acid Oxidation in Diabetic Kidney Disease

“…For example, intranasal administration of IL-37 prevented bleomycin-induced lung fibrosis and inflammation by inhabiting MAPK, PI3K/AKT, and ERK signaling pathways to control cellular processes associated with fibrosis [ 9 , 10 ]. In addition, IL-37 transgenic (IL-37tg) mice relieved autoimmune liver diseases-related fibrosis and immune cell infiltrate via regulating the downstream of Smad3 proteins and TGF-β production [ 11 ]. Of note, current studies have also showed that IL-37tg mice could protect against high fat diet-induced obesity and insulin resistance [ 12 ] by activating AMPK [ 13 ] and by inhibiting mTOR [ 14 ] pathways, which could regulate energy metabolism.…”