The macrophage is a key cell in the pro- and anti-inflammatory response including that of the inflammatory microenvironment of malignant tumors. Much current drug development in chronic inflammatory diseases and cancer therefore focuses on the macrophage as a target for immunotherapy. However, this strategy is complicated by the pleiotropic phenotype of the macrophage that is highly responsive to its microenvironment. The plasticity leads to numerous types of macrophages with rather different and, to some extent, opposing functionalities, as evident by the existence of macrophages with either stimulating or down-regulating effect on inflammation and tumor growth. The phenotypes are characterized by different surface markers and the present review describes recent progress in drug-targeting of the surface marker CD163 expressed in a subpopulation of macrophages. CD163 is an abundant endocytic receptor for multiple ligands, quantitatively important being the haptoglobin-hemoglobin complex. The microenvironment of inflammation and tumorigenesis is particular rich in CD163⁺ macrophages. The use of antibodies for directing anti-inflammatory (e.g., glucocorticoids) or tumoricidal (e.g., doxorubicin) drugs to CD163⁺ macrophages in animal models of inflammation and cancer has demonstrated a high efficacy of the conjugate drugs. This macrophage-targeting approach has a low toxicity profile that may highly improve the therapeutic window of many current drugs and drug candidates.

Macrophages play an important role in the development of nonalcoholic fatty liver disease (NAFLD) and its progression to nonalcoholic steatohepatitis (NASH). In this study, we investigated the hepatic expression of the macrophage scavenger receptor CD163 and the plasma level of its shed soluble form (sCD163) in patients with obesity and NASH, non-NASH NAFLD (NAFL), or healthy livers (no NAFLD). Paired liver biopsies and plasma samples were collected from 61 patients with obesity (body mass index ≥35). Hepatic expression of CD163 was analyzed by immunohistochemistry and data-independent acquisition mass spectrometry, whilst plasma levels of sCD163 were determined by enzyme-linked immunosorbent assay and data-independent acquisition mass spectrometry. NAFLD stage and activity were assessed using the Kleiner fibrosis and NASH Clinical Research Network (NAS-CRN) scoring system. sCD163 turned out as a promising predictor of NASH with an area under the receiver-operating characteristic curve of 0.78 [0.65;0.92] (P = .0008). sCD163 increased with more severe NAFLD both in univariate (odds ratio [OR] = 3.31[1.80;6.11], P < .001) and multivariable ordinal logistic regression adjusting for NAFLD risk factors (OR = 2.02 [1.03;3.97], P = .042). On the other hand, hepatic expression of CD163 was negatively associated with more severe NAFLD in univariate ordinal logistic regression determined by immunohistochemistry (OR = 0.91[0.84;0.98], P = .015) and proteomics (OR = 0.13[0.02;0.80], P = .028). Taking NAFLD risk factors into account, hepatic expression of CD163 was only associated with the fibrosis stage (OR = 0.01 [0.0003;0.21], P = .004). Accordingly, hepatic CD163 surface expression and sCD163 were negatively correlated (rho = −0.478, P = .0001). An increased plasma sCD163 and a concurrent decreased hepatic expression of CD163 are strongly associated with NAFLD in obese patients.

Diet and weight loss remain the primary treatment for most patients with metabolic dysfunction-associated fatty liver disease (MASLD), with one recent drug therapy approved for severe cases. However, a significant need remains for non-invasive tests (NITs) that can assist clinicians in evaluating treatment response. We aimed to explore the ability of several NITs to reflect a change of at least one point in histologic non-alcoholic fatty liver disease (NAFLD) Activity Score (NAS). This study explores biomarkers reflecting treatment response in 173 patients from secondary care with type 2 diabetes or severe obesity, all of whom underwent repeated liver biopsies and blood samples. We measured soluble triggering receptor expressed on myeloid cells 2 (TREM2), collagen markers PRO-C3, PRO-C4, PRO-C6, PRO-C8, and PRO-C18L and liver stiffness measured by FibroScan, FAST-score, and homeostatic model assessment of insulin resistance (HOMA-IR). We studied biomarker changes and their capacity to reflect liver biopsy alterations in two distinct cohorts, using comparative paired analyses and multivariable logistic regression to evaluate the results. Mean age was 52 years (±12), 38% male, 52% had NAS ≥3 at baseline (90/173), 70% had F0–F1 fibrosis, and 23% (39/173) had metabolic dysfunction-associated steatohepatitis. Significant differences were seen in sTREM2, PRO-C3, HOMA-IR, and FAST-score levels by NAS changes (worsened, no-change, improved) (p = 0.0001). In multivariable analysis, sTREM2 + PRO-C3 and HOMA-IR predicted NAS improvement (AUROC >0.75), with an odds ratio of 1.13 for each unit decrease (p = 0.001, 95% CI 1.04–1.21). FIB-4 and non-alcoholic fatty liver disease fibrosis score (NFS) did not reflect NAS improvement (AUROC <0.60, OR <1.05, p >0.5). sTREM2, PRO-C3, and HOMA-IR indicate NAS improvement and warrant further investigation as surrogate markers for gauging intervention response. Non-invasive tests (NITs) will play a crucial role in monitoring treatment responses in metabolic dysfunction-associated steatotic liver disease, providing a viable alternative to liver biopsies. Our study investigates whether NITs reflect histological responses based on changes in the non-alcoholic fatty liver disease (NAFLD) activity score (NAS) in patients with type 2 diabetes mellitus or obesity. We used non-invasive markers, some corresponding to different biological aspects of disease severity. We found that reductions in certain NIT levels correlate well with NAS reduction and composite histological improvements (lobular inflammation and ballooning). Combining soluble triggering receptor expressed on myeloid cells 2, PRO-C3, or homeostatic model assessment of insulin resistance enhances the potential for monitoring NAS improvement. ClinicalTrials.gov (NCT03068078; NCT03535142).

Sustained and excessive consumption of dietary lipids and sugars can lead to hepatic steatosis triggering metabolic dysfunction–associated steatohepatitis (MASH) characterized by inflammation and hepatocellular damage. The activation of macrophages is suggested to play an important role in the pathogenesis of MASH. Liver macrophages have a high expression of the macrophage-specific scavenger receptor CD163, but during MASH development CD163 undergoes increased shedding and downregulated expression in the liver. In this study, we investigate the relation between the expression of CD163 and early hepatic steatosis in mice. The time-dependent relation between steatosis and CD163 expression was evaluated by staining of liver specimens from male mice after 0, 5, 15, or 25 weeks of Western diet (WD) feeding. To evaluate the impact of CD163 on the early development of hepatic steatosis, we compared CD163 knockout mice and wild-type littermates fed on WD or chow diet for 8 weeks. Besides staining of liver specimens, plasma cytokines were measured, the transcriptome was analyzed by bulk RNA sequencing and liver macrophages were evaluated by flow cytometry. CD163 expression decreased in parallel to the development of hepatic steatosis in WD-fed mice. WD-fed CD163 knockout mice developed more pronounced hepatic steatosis compared to CD163 wild-type littermates after 8 weeks; however, the number of macrophages, systemic cytokine levels, and transcriptome were unaffected by the genotype. A protective role (direct or indirect) of CD163 on early development of hepatic steatosis was indicated by the finding that the severity of steatosis was significantly stronger in CD163 knockout mice. Furthermore, it underlines the importance of macrophages in lipid-driven liver disease.