The CCL2/CCR2 axis is related to primary non-response to infliximab therapy in patients with Crohn’s disease

Abstract

Abstract Background: Nearly 30% of patients with Crohn's disease (CD) are primary non-response (PNR) to anti-tumor necrosis factor-α (TNF-α) therapy, however, the mechanisms still remain unclear. TNF-α is mainly secreted by macrophages which recruited by the CCL2/CCR2 axis. We inferred that PNR to infliximab may be correlated with the CCL2/CCR2 axis. Methods: The dataset "GSE52746" including 19 responders and 17 PNR to infliximab was downloaded from Gene Expression Omnibus. The gene expressions were identified by differential gene analysis (DGA) between the two groups. Immune infiltration analysis and functional enrichment were used to determine the differential pathways. The CCL2 and CCR2 mRNA expressions were detected by quantitative PCR in the intestinal biopsy specimens from 11 responders and 13 PNR patients. The numbers of CD68+ macrophages in intestinal mucosa were determined by immunohistochemistry (IHC) staining. Results: DGA identified 1395 up-regulated and 308 down-regulated genes in the primary non-responders. Compared with the responders, CCL2 and CCR2 expression were significantly upregulated, accompanied by the larger amount of immune cells accumulated in the intestinal mucosa (P<0.05). The signaling pathways related to immune cell migration were markedly enriched in the patients of PNR to infliximab (P<0.05). The significantly higher expressions of CCL2 mRNA (P<0.0001) and CCR2 mRNA (P=0.0072) were validated in the intestinal mucosa from 11 non-responders compared with that from 13 responders. Correspondingly, the numbers of CD68+ macrophages were significantly accumulated in the mucosal tissue of non-responders (P=0.006). Conclusion: The enhanced CCL2/CCR2 axis recruited by accumulated macrophages in inflammatory intestinal mucosa is closely related with PNR to infliximab in CD patients. Our results provide a potential mechanism on anti-TNF treatment failure.