Intermediate Monocytes in Acute Alcoholic Hepatitis Are Functionally Activated and Induce IL-17 Expression in CD4+ T Cells

Abstract

In humans, the three main circulating monocyte subsets are defined by their relative cell surface expression of CD14 and CD16. They are all challenging to study because their characteristics are strongly context specific, and this has led to a range of conflicting reports about their function, which is especially so for CD14++CD16+ (intermediate) monocytes. Ex vivo cultures are also often confounded by the concomitant use of immunosuppressive drugs. We therefore sought to characterize the phenotype and function of intermediate monocytes in the setting of acute inflammation prior to treatment in a cohort of 41 patients with acute alcoholic hepatitis (AH). Circulating intermediate monocytes were enriched in patients with AH and had an activated phenotype with enhanced expression of CCR2 and CD206 compared with healthy controls. Proinflammatory cytokine expression, including IL-1β and IL-23, was also higher than in healthy controls, but both classical (CD14++CD16−) and intermediate monocytes in AH were refractory to TLR stimulation. Compared with healthy controls, both AH monocyte subsets had greater phagocytic capacity, enhanced ability to drive memory T cell proliferation in coculture, and skewed CD4+ T cells to express an increased ratio of IL-17/IFN-γ. Furthermore, liver tissue from AH patients demonstrated an enrichment of monocytes including the intermediate subset compared with controls. These data demonstrate that intermediate monocytes are expanded, functionally activated, induce CD4+ T cell IL-17 expression, and are enriched in the liver of patients with AH.

Alcohol’s Impact on the Gut and Liver

“…In addition to an activated pro-inflammatory immune response to alcohol, patients with alcoholic hepatitis have evidence of immune dysfunction. The activation of monocytes by gut-derived PAMPs leads to T cell exhaustion with reduced numbers of anti-inflammatory IL-10 producing T cells and functionally impaired monocytes and neutrophils [ 46 , 47 ].…”

“…cytes by gut-derived PAMPs leads to T cell exhaustion with reduced numbers of antiinflammatory IL-10 producing T cells and functionally impaired monocytes and neutrophils [46,47].…”

Glucocorticoid treatment in patients with newly diagnosed immune thrombocytopenia switches CD14++CD16+ intermediate monocytes from a pro‐inflammatory to an anti‐inflammatory phenotype

“…12 In many autoimmune conditions, I-MCs are enriched 13 and in the context of inflammation drive enhanced memory T-cell proliferation and inflammatory cytokine expression. 14,15 CD16 + MCs from patients with ITP have been shown to specifically promote the expansion of IFNc + CD4 + T cells and concomitantly inhibit the proliferation of Tregs, 16 providing evidence that MCs shape T-cell responses in ITP. However, a detailed MC phenotype in untreated, newly diagnosed patients with active ITP has not yet been described.…”

“…Human MCs are classified into three subsets based on their cell surface expression of CD14 [lipopolysaccharide (LPS) co‐receptor] and CD16 [activatory Fc gamma receptor III (FcγRIII)] into classical (C‐MCs; CD14 ++ CD16 − ), intermediate (I‐MCs; CD14 ++ CD16 + ) and non‐classical (NC‐MCs; CD14 + CD16 ++ ) MCs 12 . In many autoimmune conditions, I‐MCs are enriched 13 and in the context of inflammation drive enhanced memory T‐cell proliferation and inflammatory cytokine expression 14,15 . CD16 + MCs from patients with ITP have been shown to specifically promote the expansion of IFN‐γ + CD4 + T cells and concomitantly inhibit the proliferation of Tregs, 16 providing evidence that MCs shape T‐cell responses in ITP.…”

Exploration of the Link Between COVID-19 and Alcoholic Hepatitis from the Perspective of Bioinformatics and Systems Biology

“…Among them, the IL-17 pathway has been observed to upregulate expression in the serum of COVID-19 patients in multiple studies and has been speculated to induce a cytokine storm to promote inflammation, while its inhibitors have been observed to attenuate or even prevent cytokine storms (40). This process has also been reported in the pathogenesis of AH, through intermediate monocytes expansion, functional activation, induction of CD4 T cell IL-17 expression, and enrichment in the liver of AH patients to obtain greater phagocytic capacity (41). Reactom pathway and Wikipathway analysis also found that the common mechanism of AH and COVID-19 exists in pathways such as mediating chemotaxis effects, complementing the first two analyses.…”