Emergence of immunoregulatory Ym1 ⁺ Ly6C ^hi monocytes during recovery phase of tissue injury

Abstract

Ly6C hi monocytes migrate to injured sites and induce inflammation in the acute phase of tissue injury. However, once the causes of tissue injury are eliminated, monocyte-derived macrophages contribute to the resolution of inflammation and tissue repair. It remains unclear whether the emergence of these immunoregulatory macrophages is attributed to the phenotypic conversion of inflammatory monocytes in situ or to the recruitment of bone marrowderived regulatory cells de novo. Here, we identified a subpopulation of Ly6C hi monocytes that contribute to the resolution of inflammation and tissue repair. Ym1 + Ly6C hi monocytes greatly expanded in bone marrow during the recovery phase of systemic inflammation or tissue injury. Ym1 + Ly6C hi monocytes infiltrating into an injured site exhibited immunoregulatory and tissue-reparative phenotypes. Deletion of Ym1 + Ly6C hi monocytes resulted in delayed recovery from colitis. These results demonstrate that a distinct monocyte subpopulation destined to act in immunoregulation is generated in bone marrow and participates in resolution of inflammation and tissue repair. Emergence of immunoregulatory Ym1 + Ly6C hi monocytes during recovery phase of tissue injury.

Recruitment of hepatic macrophages from monocytes is independent of IL‐4Rα but is associated with ablation of resident macrophages in schistosomiasis

“…Importantly, CD11b hi Mϕ were the main IL-4Rα-responsive cells producing large amounts of Ym1, Relm-α and Arg1 whereas the expression of these AAMϕ signature proteins was significantly reduced in S. mansoni-infected Il4ra −/lox lyz2 Cre mice. Interestingly, Ym1 or Relm-α were not upregulated in CD11b lo KCs, a result that is supported by a recent report using reporter Ym1-Venus mice showing that liver Mϕ in naive mice do not express Ym1, as opposed to lung alveolar Mϕ [35]. Ablation of CCR2-dependent monocytes after DT treatment of CCR2 DTR mice during schistosomiasis resulted in impaired granuloma formation, weight loss and death [15], further highlighting the essential role of CD11b hi Mϕ derived from recruited monocytes for the regulation of liver granulomatous inflammation.…”

“…While Relm‐α and Arg1 have been identified as negative regulators of type 2 inflammation , the role of Ym1 is less clear. Importantly, a recent report identified a subpopulation of Ym1 + Ly6C hi monocytes that expanded in response to LPS administration and contributed to recovery from DSS‐induced colitis . Although Ly6C hi monocytes represented a large proportion of cells in the inflamed livers, these cells did not significantly upregulate Ym1 after S. mansoni infection; CD11b hi Mφ together with neutrophils were the main source of Ym1.…”

Neutrophil–macrophage cooperation and its impact on tissue repair

“…This transition was further shown to be IL‐4/IL‐10 dependent . Interestingly, it has recently been described in a model of colitis that regulatory Ym1 + Ly6C hio monocytes can expand in bone marrow at the beginning of the resolution phase, and then leave the bone marrow to enter the damaged colon, rather than acquire their phenotype in the injured tissue.…”

Macrophage immunomodulation in chronic osteolytic diseases—the case of periodontitis

“…As inflammation enters its resolution phase, recruited monocytes give rise to rMac cells that share M1 and M2 features including reduced production of proinflammatory cytokines, antigen processing/presentation and efferocytosis . Adoption of a resolving phenotype occurs in response to anti‐inflammatory cytokines IL‐4 and IL‐13, primarily produced by Th2 lymphocytes and plasma/B cells, SPMs that activate surface GPCR receptors (e.g., GPR18, GPR32, GPR120, and ERV1) in Macs, or anti‐diabetic therapeutic agents such as thiazolidinediones (TZD; e.g., rosiglitazone) that activate PPAR‐γ in monocytes .…”

“…95,96 As inflammation enters its resolution phase, recruited monocytes give rise to rMac cells that share M1 and M2 features including reduced production of proinflammatory cytokines, antigen processing/presentation and efferocytosis. 97,98 Adoption of a resolving phenotype occurs in response to anti-inflammatory cytokines IL-4 and IL-13, primarily produced by Th2 lymphocytes and plasma/B cells, SPMs that activate surface GPCR receptors (e.g., GPR18, GPR32, GPR120, and ERV1) in Macs, or anti-diabetic therapeutic agents such as thiazolidinediones (TZD; e.g., rosiglitazone) that activate PPARin monocytes. 99,100 rMacs adopt a IL-12 low IL-10 high phenotype with increased phagocytic activity, high surface expression of scavenging receptors, production of ornithine and polyamines through the arginase pathway, reduced proinflammatory cytokine (IL-1 , IL-6, IL-12, and TNF-) and cyclooxygenase 2 (COX2) and increased antiinflammatory cytokine (IL-1RA, IL-10, and TGF ) production.…”