Human intestinal pro-inflammatory CD11chighCCR2+CX3CR1+ macrophages, but not their tolerogenic CD11c-CCR2-CX3CR1- counterparts, are expanded in inflammatory bowel disease

Abstract

Although macrophages (Mϕ) maintain intestinal immune homoeostasis, there is not much available information about their subset composition, phenotype and function in the human setting. Human intestinal Mϕ (CD45⁺HLA-DR⁺CD14⁺CD64⁺) can be divided into subsets based on the expression of CD11c, CCR2 and CX3CR1. Monocyte-like cells can be identified as CD11c^highCCR2⁺CX3CR1⁺ cells, a phenotype also shared by circulating CD14⁺ monocytes. On the contrary, their Mϕ-like tissue-resident counterparts display a CD11c^-CCR2^-CX3CR1^- phenotype. CD11c^high monocyte-like cells produced IL-1β, both in resting conditions and after LPS stimulation, while CD11c^- Mϕ-like cells produced IL-10. CD11c^high pro-inflammatory monocyte-like cells, but not the others, were increased in the inflamed colon from patients with inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis. Tolerogenic IL-10-producing CD11c^- Mϕ-like cells were generated from monocytes following mucosal conditioning. Finally, the colonic mucosa recruited circulating CD14⁺ monocytes in a CCR2-dependent manner, being such capacity expanded in IBD. Mϕ subsets represent, therefore, transition stages from newly arrived pro-inflammatory monocyte-like cells (CD11c^highCCR2⁺CX3CR1⁺) into tolerogenic tissue-resident (CD11c^-CCR2^-CX3CR1^-) Mϕ-like cells as reflected by the mucosal capacity to recruit circulating monocytes and induce CD11c^- Mϕ. The process is nevertheless dysregulated in IBD, where there is an increased migration and accumulation of pro-inflammatory CD11c^high monocyte-like cells.